sections of research protocol

Write an Error-free Research Protocol As Recommended by WHO: 21 Elements You Shouldn’t Miss!

Principal Investigator: Did you draft the research protocol?

Student: Not yet. I have too many questions about it. Why is it important to write a research protocol? Is it similar to research proposal? What should I include in it? How should I structure it? Is there a specific format?

Researchers at an early stage fall short in understanding the purpose and importance of some supplementary documents, let alone how to write them. Let’s better your understanding of writing an acceptance-worthy research protocol.

Table of Contents

What Is Research Protocol?

The research protocol is a document that describes the background, rationale, objective(s), design, methodology, statistical considerations and organization of a clinical trial. It is a document that outlines the clinical research study plan. Furthermore, the research protocol should be designed to provide a satisfactory answer to the research question. The protocol in effect is the cookbook for conducting your study

Why Is Research Protocol Important?

In clinical research, the research protocol is of paramount importance. It forms the basis of a clinical investigation. It ensures the safety of the clinical trial subjects and integrity of the data collected. Serving as a binding document, the research protocol states what you are—and you are not—allowed to study as part of the trial. Furthermore, it is also considered to be the most important document in your application with your Institution’s Review Board (IRB).

It is written with the contributions and inputs from a medical expert, a statistician, pharmacokinetics expert, the clinical research coordinator, and the project manager to ensure all aspects of the study are covered in the final document.

Is Research Protocol Same As Research Proposal?

Often misinterpreted, research protocol is not similar to research proposal. Here are some significant points of difference between a research protocol and a research proposal:

What Are the Elements/Sections of a Research Protocol?

According to Good Clinical Practice guidelines laid by WHO, a research protocol should include the following:

1. General Information

• Protocol title, protocol identifying number (if any), and date.
• Name and address of the funder.
• Name(s) and contact details of the investigator(s) responsible for conducting the research, the research site(s).
• Responsibilities of each investigator.
• Name(s) and address(es) of the clinical laboratory(ies), other medical and/or technical department(s) and/or institutions involved in the research.

2. Rationale & Background Information

• The rationale and background information provides specific reasons for conducting the research in light of pertinent knowledge about the research topic.
• It is a statement that includes the problem that is the basis of the project, the cause of the research problem, and its possible solutions.
• It should be supported with a brief description of the most relevant literatures published on the research topic.

3. Study Objectives

• The study objectives mentioned in the research proposal states what the investigators hope to accomplish. The research is planned based on this section.
• The research proposal objectives should be simple, clear, specific, and stated prior to conducting the research.
• It could be divided into primary and secondary objectives based on their relativity to the research problem and its solution.

4. Study Design

• The study design justifies the scientific integrity and credibility of the research study.
• The study design should include information on the type of study, the research population or the sampling frame, participation criteria (inclusion, exclusion, and withdrawal), and the expected duration of the study.

5. Methodology

• The methodology section is the most critical section of the research protocol.
• It should include detailed information on the interventions to be made, procedures to be used, measurements to be taken, observations to be made, laboratory investigations to be done, etc.
• The methodology should be standardized and clearly defined if multiple sites are engaged in a specified protocol.

6. Safety Considerations

• The safety of participants is a top-tier priority while conducting clinical research .
• Safety aspects of the research should be scrutinized and provided in the research protocol.

7. Follow-up

• The research protocol clearly indicate of what follow up will be provided to the participating subjects.
• It must also include the duration of the follow-up.

8. Data Management and Statistical Analysis

• The research protocol should include information on how the data will be managed, including data handling and coding for computer analysis, monitoring and verification.
• It should clearly outline the statistical methods proposed to be used for the analysis of data.
• For qualitative approaches, specify in detail how the data will be analysed.

9. Quality Assurance

• The research protocol should clearly describe the quality control and quality assurance system.
• These include GCP, follow up by clinical monitors, DSMB, data management, etc.

10. Expected Outcomes of the Study

• This section indicates how the study will contribute to the advancement of current knowledge, how the results will be utilized beyond publications.
• It must mention how the study will affect health care, health systems, or health policies.

11. Dissemination of Results and Publication Policy

• The research protocol should specify not only how the results will be disseminated in the scientific media, but also to the community and/or the participants, the policy makers, etc.
• The publication policy should be clearly discussed as to who will be mentioned as contributors, who will be acknowledged, etc.

12. Duration of the Project

• The protocol should clearly mention the time likely to be taken for completion of each phase of the project.
• Furthermore a detailed timeline for each activity to be undertaken should also be provided.

13. Anticipated Problems

• The investigators may face some difficulties while conducting the clinical research. This section must include all anticipated problems in successfully completing their projects.
• Furthermore, it should also provide possible solutions to deal with these difficulties.

14. Project Management

• This section includes detailed specifications of the role and responsibility of each investigator of the team.
• Everyone involved in the research project must be mentioned here along with the specific duties they have performed in completing the research.
• The research protocol should also describe the ethical considerations relating to the study.
• It should not only be limited to providing ethics approval, but also the issues that are likely to raise ethical concerns.
• Additionally, the ethics section must also describe how the investigator(s) plan to obtain informed consent from the research participants.
• This section should include a detailed commodity-wise and service-wise breakdown of the requested funds.
• It should also include justification of utilization of each listed item.

17. Supplementary Support for the Project

• This section should include information about the received funding and other anticipated funding for the specific project.

18. Collaboration With Other Researchers or Institutions

• Every researcher or institute that has been a part of the research project must be mentioned in detail in this section of the research protocol.

19. Curriculum Vitae of All Investigators

• The CVs of the principal investigator along with all the co-investigators should be attached with the research protocol.
• Ideally, each CV should be limited to one page only, unless a full-length CV is requested.

20. Other Research Activities of Investigators

• A list of all current research projects being conducted by all investigators must be listed here.

21. References

• All relevant references should be mentioned and cited accurately in this section to avoid plagiarism.

How Do You Write a Research Protocol? (Research Protocol Example)

Main Investigator    

Number of Involved Centers (for multi-centric studies)

Indicate the reference center

Title of the Study

Protocol ID (acronym)

Keywords (up to 7 specific keywords)

Study Design

Mono-centric/multi-centric

Perspective/retrospective

Controlled/uncontrolled

Open-label/single-blinded or double-blinded

Randomized/non-randomized

n parallel branches/n overlapped branches

Experimental/observational

Endpoints (main primary and secondary endpoints to be listed)

Expected Results                                                

Analyzed Criteria

Main variables/endpoints of the primary analysis

Main variables/endpoints of the secondary analysis

Safety variables

Health Economy (if applicable)

Visits and Examinations

Therapeutic plan and goals

Visits/controls schedule (also with graphics)

Comparison to treatment products (if applicable)

Dose and dosage for the study duration (if applicable)

Formulation and power of the studied drugs (if applicable)

Method of administration of the studied drugs (if applicable)

Informed Consent

Study Population

Short description of the main inclusion, exclusion, and withdrawal criteria

Sample Size

Estimated Duration of the Study

Safety Advisory

Classification Needed

Requested Funds

Additional Features (based on study objectives)

Click Here to Download the Research Protocol Example/Template

Be prepared to conduct your clinical research by writing a detailed research protocol. It is as easy as mentioned in this article. Follow the aforementioned path and write an impactful research protocol. All the best!

Clear as template! Please, I need your help to shape me an authentic PROTOCOL RESEARCH on this theme: Using the competency-based approach to foster EFL post beginner learners’ writing ability: the case of Benin context. I’m about to start studies for a master degree. Please help! Thanks for your collaboration. God bless.

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Article Contents

Introduction, contents of a research study protocol, conflict of interest statement, how to write a research study protocol.

• Article contents
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Julien Al Shakarchi, How to write a research study protocol, Journal of Surgical Protocols and Research Methodologies , Volume 2022, Issue 1, January 2022, snab008, https://doi.org/10.1093/jsprm/snab008

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A study protocol is an important document that specifies the research plan for a clinical study. Many funders such as the NHS Health Research Authority encourage researchers to publish their study protocols to create a record of the methodology and reduce duplication of research effort. In this paper, we will describe how to write a research study protocol.

A study protocol is an essential part of a research project. It describes the study in detail to allow all members of the team to know and adhere to the steps of the methodology. Most funders, such as the NHS Health Research Authority in the United Kingdom, encourage researchers to publish their study protocols to create a record of the methodology, help with publication of the study and reduce duplication of research effort. In this paper, we will explain how to write a research protocol by describing what should be included.

Introduction

The introduction is vital in setting the need for the planned research and the context of the current evidence. It should be supported by a background to the topic with appropriate references to the literature. A thorough review of the available evidence is expected to document the need for the planned research. This should be followed by a brief description of the study and the target population. A clear explanation for the rationale of the project is also expected to describe the research question and justify the need of the study.

Methods and analysis

A suitable study design and methodology should be chosen to reflect the aims of the research. This section should explain the study design: single centre or multicentre, retrospective or prospective, controlled or uncontrolled, randomised or not, and observational or experimental. Efforts should be made to explain why that particular design has been chosen. The studied population should be clearly defined with inclusion and exclusion criteria. These criteria will define the characteristics of the population the study is proposing to investigate and therefore outline the applicability to the reader. The size of the sample should be calculated with a power calculation if possible.

The protocol should describe the screening process about how, when and where patients will be recruited in the process. In the setting of a multicentre study, each participating unit should adhere to the same recruiting model or the differences should be described in the protocol. Informed consent must be obtained prior to any individual participating in the study. The protocol should fully describe the process of gaining informed consent that should include a patient information sheet and assessment of his or her capacity.

The intervention should be described in sufficient detail to allow an external individual or group to replicate the study. The differences in any changes of routine care should be explained. The primary and secondary outcomes should be clearly defined and an explanation of their clinical relevance is recommended. Data collection methods should be described in detail as well as where the data will be kept secured. Analysis of the data should be explained with clear statistical methods. There should also be plans on how any reported adverse events and other unintended effects of trial interventions or trial conduct will be reported, collected and managed.

Ethics and dissemination

A clear explanation of the risk and benefits to the participants should be included as well as addressing any specific ethical considerations. The protocol should clearly state the approvals the research has gained and the minimum expected would be ethical and local research approvals. For multicentre studies, the protocol should also include a statement of how the protocol is in line with requirements to gain approval to conduct the study at each proposed sites.

It is essential to comment on how personal information about potential and enrolled participants will be collected, shared and maintained in order to protect confidentiality. This part of the protocol should also state who owns the data arising from the study and for how long the data will be stored. It should explain that on completion of the study, the data will be analysed and a final study report will be written. We would advise to explain if there are any plans to notify the participants of the outcome of the study, either by provision of the publication or via another form of communication.

The authorship of any publication should have transparent and fair criteria, which should be described in this section of the protocol. By doing so, it will resolve any issues arising at the publication stage.

Funding statement

It is important to explain who are the sponsors and funders of the study. It should clarify the involvement and potential influence of any party. The sponsor is defined as the institution or organisation assuming overall responsibility for the study. Identification of the study sponsor provides transparency and accountability. The protocol should explicitly outline the roles and responsibilities of any funder(s) in study design, data analysis and interpretation, manuscript writing and dissemination of results. Any competing interests of the investigators should also be stated in this section.

A study protocol is an important document that specifies the research plan for a clinical study. It should be written in detail and researchers should aim to publish their study protocols as it is encouraged by many funders. The spirit 2013 statement provides a useful checklist on what should be included in a research protocol [ 1 ]. In this paper, we have explained a straightforward approach to writing a research study protocol.

None declared.

Chan   A-W , Tetzlaff   JM , Gøtzsche   PC , Altman   DG , Mann   H , Berlin   J , et al.    SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials . BMJ   2013 ; 346 : e7586 .

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Tips for Writing a Research Protocol

A brilliant advanced practitioner colleague, whose article you will find in this issue, asked whether JADPRO would publish her successfully funded grant application. When I asked about her motivation to become a researcher and seek grant funding after years of a successful clinical career, she had the most astonishing reply. “Physicians can be physician scientists, and I wanted to be a nurse practitioner scientist.” Her motivation made me wonder how many other advanced practitioners (APs) share the same desire: To strike a balance between conducting innovative research and maintaining patient care responsibilities. Indeed, her career path seemed remarkably similar to mine.

I have known Sara M. Tinsley-Vance, PhD, APRN, AOCN®, of Moffitt Cancer Center, for years, and have been fully aware of her extensive experience in the diagnosis and management of older adults with acute myeloid leukemia. Knowledge gained through her clinical work undoubtedly drove her passion to conduct innovative symptom management and quality-of-life research. Personal connections with patients and families led to her desire to retain her clinical practice. As you can imagine, time was a barrier to balancing these two areas of her profession.

In this issue, Dr. Tinsley-Vance provides a window into her career path. She found a unique approach to achieve her goals through writing a business plan and securing research funding for protected time. Most of you who are reading this are likely wondering how to achieve a professional model similar to the one Dr. Tinsley-Vance has. In previous issues, I wrote about the differences between quality improvement projects and clinical research, and tips for publishing ( Faiman, 2021 , 2022 ), but until now, I have not covered protocol writing and the grant funding processes.

WRITING A PROTOCOL

A protocol is the detailed plan of the study and an essential component of research. The steps to take before one decides to write the research protocol can be overwhelming, but even babies need to take their first steps. Draw from your professional experiences, discuss your desire to conduct research, and you might be surprised by the support from your workplace! From topic discovery (What is your passion?) to literature review (Was this topic studied elsewhere and, if so, how was the research conducted? What methods and instruments were used?), you will likely need to assemble a research team and obtain as much support as possible for data collection and funding. See Table 1 for a brief synopsis of key considerations. You can look for funding from sources such as the National Institutes of Health, National Institute of Nursing Research, National Cancer Institute, National Comprehensive Cancer Network, or Oncology Nursing Society.

Consider adding to existing knowledge on your topic of interest by conducting your very own, well-designed research or quality improvement project. I hope to see your abstract and poster presented at a future JADPRO Live meeting, and the research outcome published in JADPRO !

IN THIS ISSUE

In addition to Dr. Tinsley-Vance's article on a research strategy for a quality-of-life decision-making model for older patients with acute myeloid leukemia, read about findings on the relationship between distress levels and communication needs of neuro-oncology patients in this issue. In the Review department, learn about the management of ocular toxicities in patients receiving belantamab mafodotin; although this drug was withdrawn from the US market, there may still be patients receiving it in clinical trials. You will also find an article on the complex topic of medical aid in dying, and the provider's role in this ethical dilemma. Read a case study on managing gastrointestinal stromal tumors, with an emphasis on fourth-line options. An article in this issue investigates cost analysis data on the value of oncology pharmacists. Finally, test your knowledge on a patient with neuroendocrine malignancy and liver metastases presenting with symptoms including abdominal pain, diarrhea, abdominal bloating, and weight loss.

• Faiman, B. (2021). Publish or perish . Journal of the Advanced Practitioner in Oncology , 12 ( 5 ), 463–464. 10.6004/jadpro.2021.12.5.1 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Faiman, B. (2022). Insights into the publishing process . Journal of the Advanced Practitioner in Oncology , 13 ( 7 ), 653–654. 10.6004/jadpro.2022.13.7.1 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

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Published peer-reviewed protocols 

A research protocol is a detailed study design or set of instructions for carrying out a specific experimental process or procedure.

Benefits of Published Protocols

Peer-review of protocols supports rigorous, high-quality research, while publication increases discoverability, supports reproducibility, and recognizes the importance of the scientific work. Articles published under an Open Access license are freely available for anyone, anywhere in the world to discover, read, distribute or reuse at no cost. For that reason, Open Access articles are more widely read than subscription research.

Improve  your approach Expert peer review feedback can help to refine and shape your protocol, promoting usability and efficiency.

Earn readers’ trust  It’s difficult to reproduce results—or even confirm the question a study is designed to answer—based on a research article alone. Protocols show that you did what you set out to do, and how you went about it.

Expand your publication record  Protocols take time and thought to develop; claim academic credit for your efforts through formal publication. 

Help you field move faster Published protocols are discoverable and accessible, enabling other researchers to adapt and build upon your accomplishments.

Discover how publishing protocols helps increase research visibility

PLOS authors share how they have created more visibility and impact for their research with published Lab Protocols.

How reproducible is your research?

Take our self-assessment to see your reproducibility score.

Read more about published protocols

When it comes to methods sharing, Lab Protocols at PLOS ONE offer researchers the best of both worlds: a platform specifically designed for step-by-step protocols, and a peer-reviewed publication in a well-regarded journal.

Our ongoing partnership with protocols.io led to a new and exciting PLOS ONE article type, Lab Protocols, which offers a new avenue to share research in-line with the principles of Open Science.

PLOS ONE’s array of publication options that push the boundaries of Open Science continues to expand. We’re happy to announce two new article types that improve reproducibility and transparency, and allow researchers to receive credit for their contributions to study design: Lab Protocols and Study Protocols.

Lab Protocols

PLOS ONE  is committed to pushing the boundaries of Open Science by improving the reproducibility and transparency of scientific research. In collaboration with protocols.io, Lab Protocols offer authors the opportunity to share their peer reviewed step-by-step protocols with the community whilst receiving credit for their contributions.

Discover your options for publishing protocols at PLOS

You devote countless hours to the development of a study design or research method. Each deserves more than a footnote. We invite you to submit your protocols for peer review and formal publication. Choose the publication option that best fits your research needs.

Study Protocols

Study protocols describe detailed plans and proposals for research projects that have not yet generated results. They consist of a single article in PLOS ONE that can be referenced in future papers.

Already common in the health sciences, sharing a study’s design and analysis plan before the research is carried out improves transparency and coordinates effort.

Lab protocols describe reusable methodologies in all fields of study. They consist of two interlinked components:

• A step-by-step protocol posted to protocols.io , with access to specialized tools for communicating technical details, including reagents, measurements, and formulae.
• A peer-reviewed PLOS ONE article contextualizing the protocol, with sections discussing applications, limitations, expected results and sample datasets.

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Protocol Elements

The following outlines the basic elements of a research protocol. The IRB templates will provide more specific requirements. 

Table of Contents

Introduction/abstract, objectives and rationale, methods and procedures, subject population selection and inclusion/exclusion criteria, risks and benefits, provisions for treatment of adverse events, subject recruitment, review preparatory to research and recruitment.

• Subject Compensation/Reimbursement

Study Management and Personnel

• Confidentiality and Data Storage

Data Analysis and Evaluation Techniques

• Bibliography

Protocols coming from industry or protocols for multi-site studies typically include a table of contents. The UVA IRB protocol templates created by Protocol Builder do not require a table of contents. 

The introduction should indicate the specific reasons or rationale for performing the study, the hypotheses, study design (  e.g.  , record review, questionnaire, specimen collection, interview, prospective evaluation of a drug or device), and an overview of the literature on comparable studies. If applicable, Principal Investigators should briefly describe the intervention, treatment, drugs, or devices to be used. 

A hypothesis is a tentative statement that proposes a possible explanation to some phenomenon or event. A useful hypothesis is a testable statement which may include a prediction. The key word is testable. That is, you will perform a test of how two variables might be related. This is when you are doing a real experiment. You are testing variables. 

The objectives of the study should be: 

• based on the research question(s); 
• limited in scope and number; 
• based on specific quantifiable endpoints; and 
• congruent with the study design. 

The scientific rationale should provide enough information to answer the question, "Why should this study be done?" It should contain a referenced review of the literature specifically pertaining to the reasons for the current study and previous investigations that lead the investigator to pose the specific question. In addition, it should include a justification of the research design and the use of any placebos. 

This section describes the study design, the study population, the research intervention, if applicable, sample selection, and an appropriate analytic plan. Specific recommendations for presenting study methods are presented below. 

For Clinical Research 

The Methods section for clinical study protocols evaluating a drug, device or a treatment modality should explain the treatment plan. Baseline diagnostic tests, initial laboratory assessments for determining eligibility of a potential subject to enter the trial, and any procedures, physical exams, tests, interviews, videotapes, and the amount of time the subject will be involved in the study should be detailed. Principal Investigators should consider including a table or schematic of study events by visit to clarify for the IRB reviewers what tests, procedures, etc. will be done and when they will be done. 

Principal Investigators should make clear which interventions and procedures are standard clinical care for the subject's condition and which are experimental or, if not experimental, are being performed solely as a result of the subject's participation in the clinical research. 

Principal Investigators should discuss (1) the procedures for monitoring the subject's condition and (2) reasons for dropping any participant from the study  (e.g.  , relapse, lack of subject compliance). 

Subject Selection and Inclusion Criteria

UVA recognizes its responsibility to create an environment in which the equitable selection of research participants is fostered. Therefore, Principal Investigators must provide the IRB the details on the proposed involvement of humans in the research. Principal Investigators must describe the number of subjects and observations necessary to obtain statistically valid results. The type of study design and the procedures for randomization, blinding, crossover, controls (positive and negative), and, washout, as applicable, must all be explained. Principal Investigators must specify the:

• characteristics of the subject population, 
• number of subjects to be enrolled (e.g. sign consent)
• number of subjects (e.g.  the number of subjects required to obtain statistically valid results), 
• age ranges of subjects, 
• health statuses of subjects, and 
• the gender composition and racial/ethnic composition of the subject population. If ethnic, racial and gender estimates are not specified, the Principal Investigator must provide a clear rationale for exclusion of this information. 

Methods for subject screening and eligibility should be described in detail. Screening for enrollment into a study entails careful evaluation of the potential subject on the basis of the criteria that are stated in the protocol. 

Subject eligibility criteria should be listed, including age, sex, race/ethnicity, and other inclusion and exclusion criteria. If a potential subject conforms to those preliminary criteria, more specific screening evaluations can be performed, such as the taking of a medical history, a physical examination, and clinical laboratory tests, such as a complete blood count with differential; blood chemistry analysis (e.g.  electrolytes, cholesterol, and triglycerides, urinalysis, an electrocardiogram, and blood pressure.)

The protocol should state the limits of acceptability for the aforementioned evaluations; for example, it should define a normal range for the clinical laboratory tests and include appropriate statements about the interpretation of those tests (e.g. statements on borderline values). 

If the proposed study may include a vulnerable or special subject population, investigators shall refer to the additional requirements for these subject populations. 

Subject Exclusion Criteria

Exclusion criteria may include such things as severity of disease, mental incompetence, use of other medication concomitantly, or presence of other diseases. Principal Investigators must explain and justify the exclusion of women and/or minority groups and children.

Women and Minorities

All research involving human subjects should be designed and conducted to include members of both genders and members of minority groups, unless a clear and compelling rationale and justification establishes that such inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. 

The NIH acknowledges clear scientific and public health reasons for specifically including members of minority groups in studies of health problems that disproportionately affect U.S. racial/ethnic minority populations. In attempting to include minority groups, Principal Investigators should assess the theoretical and/or scientific connections between race/ethnicity in the topic of study. FDA Guidelines require that subjects recruited to trials reflect the population that will receive the drug/therapeutic intervention when it is marketed or approved for administration. FDA Guidelines also recommend that "representatives of both genders be included in clinical trials in numbers adequate to allow detection of clinically significant gender related differences in drug response." 

For NIH-defined Phase I and II clinical trials, the systematic inclusion and reporting of information on women and minorities and minority subpopulations is generally required to increase the scientific base of knowledge about them. For Phase III clinical trials, the design of the trials must reflect the current state of knowledge about any clinically important gender and/or race/ethnicity differences in the response to the intervention. Evidence may include data from prior animal studies, clinical observations, metabolic studies, genetic studies, pharmacology studies, and observational, epidemiologic and other relevant studies. The nature of the evidence should be used to determine the extent to which women, men and members of minority groups and their subpopulations must be included. In addition, national statistics on the disease, disorder or condition under study and national population statistics should be used in designing Phase III clinical trials. 

Studies should employ a design with gender, racial and/or age representations appropriate to the known incidence/prevalence of the disease or condition being studied. If subjects of a certain gender, race or age group are to be excluded and it can reasonably be assumed that the drug or therapeutic intervention when approved will be administered to both sexes and all age and racial groups, the investigator  must  clearly explain and justify such exclusion. 

It is not expected that every minority group and subpopulation will be included in each study; however, broad representation and diversity are the goals, even if multiple clinics and sites are needed to accomplish it. 

Minority groups recognized by NIH include: 

• American Indian or Alaskan Native (person having origins in any of the original peoples of North America , and who maintain cultural identification through tribal affiliation or community recognition); 
• (ii) Asian or Pacific Islander (person having origins in any of the original peoples of the Far East, Southeast Asia, the Indian subcontinent or the Pacific Islands and Samoa); 
• (iii) Black, not of Hispanic origin (a person having origins in any of the black racial groups of Africa ); and 
• (iv) Hispanic (a person or Mexican, Puerto Rican, Cuban, Central or South American or other Spanish culture or origin regardless of race). 

Each minority group may contain subpopulations which are delimited by geographic origins, national origins and/or cultural differences. The minority group or subpopulation to which an individual belongs is determined by self-reporting. 

Subject Withdrawal Criteria 

A protocol shall include subject withdrawal criteria and procedures specifying 

• when and how to withdraw subjects from the trial, 
• the type and timing of data to be collected for withdrawn subjects, 
• whether and how subjects will be replaced, and 
• the follow-up for such subjects. 

If data collected for research purposes has clinical significance for individuals in the study but the data will be analyzed at another institution, resulting in substantial delay in receipt of important clinical findings affecting the subject's welfare, Principal Investigators should specify how they intend to monitor the subject locally. 

Background 

Per DHHS and FDA regulations (45 CFR 46.111 and 21 CFR 56.111) two of the required criteria for granting IRB approval of the research are: 

• Risks to subjects are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes. 
• Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB will consider only those risks and benefits that may result from the research, as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research. 

Definitions 

• Benefit: A valued or desired outcome; an advantage. 
• Risk: The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant. Federal regulations define only "minimal risk." 
• Minimal Risk: A risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily lives of the general population or during the performance of routine physical or psychological examinations or tests. 
• Minimal Risk for Research involving Prisoners: The definition of minimal risk for research involving prisoners differs somewhat from that given for non-institutionalized adults. Minimal risk is in this case is defined as, "the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives , or in the routine medical, dental or psychological examinations of healthy persons ." 

Overview of Risks and Benefits 

There are two sources of confusion in the assessment of risks and benefits. One arises from the language employed in the discussion: 

• "Risk" is a word expressing probabilities; 
• "Benefits" is a word expressing a fact or state of affairs. 

It is more accurate to speak as if both were in the realm of probability: i.e., risks and expected or anticipated benefits. 

Confusion also may arise because "risks" can refer to two quite different things: 

• those chances that specific individuals are willing to undertake for some desired goal; or 
• the conditions that make a situation harmful to a subject. 

Researchers should provide detailed information in the IRB protocol about potential risks and benefits associated with the research, and provide information about the probability, magnitude and potential harms associated with each risk. 

Risk/Benefit Assessment 

The IRB is responsible for evaluating the potential risks and weighing the probability of the risk occurring and the magnitude of harm that may result. It must then judge whether the anticipated benefit, either of new knowledge or of improved health for the research subjects, justifies inviting any person to undertake the risks. The IRB cannot approve research in which the risks are judged unreasonable in relation to the anticipated benefits. The IRB must: 

• Identify the risks associated with the research, as distinguished from the risks of therapies the subjects would receive even if not participating in research; 
• Determine that the risks will be minimized to the extent possible [see below]; 
• Identify the probable benefits to be derived from the research; 
• Determine that the risks are reasonable in relation to be benefits to subjects, if any, and the importance of the knowledge to be gained; and 
• Assure that potential subjects will be provided with an accurate and fair description (during consent) of the risks or discomforts and the anticipated benefits. 

Types of Risk to Research Subjects 

The risks to which research subjects may be exposed have been classified as physical, psychological, social, and economic. 

Physical Harms:  Medical research often involves exposure to minor pain, discomfort, or injury from invasive medical procedures, or harm from possible side effects of drugs. All of these should be considered "risks" for purposes of IRB review. Some of the adverse effects that result from medical procedures or drugs can be permanent, but most are transient. Procedures commonly used in medical research usually result in no more than minor discomfort (e.g., temporary dizziness, the pain associated with venipuncture).  Some medical research is designed only to measure more carefully the effects of therapeutic or diagnostic procedures applied in the course of caring for an illness. Such research may not entail any significant risks beyond those presented by medically indicated interventions. On the other hand, research designed to evaluate new drugs or procedures may present more than minimal risk, and, on occasion, can cause serious or disabling injuries.  Psychological Harms:  Participation in research may result in undesired changes in thought processes and emotion (e.g., episodes of depression, confusion, or hallucination resulting from drugs, feelings of stress, guilt, and loss of self-esteem). These changes may be transitory, recurrent, or permanent. Most psychological risks are minimal or transitory, but some research has the potential for causing serious psychological harm.  Stress and feelings of guilt or embarrassment may arise simply from thinking or talking about one's own behavior or attitudes on sensitive topics such as drug use, sexual preferences, selfishness, and violence. These feelings may be aroused when the subject is being interviewed or filling out a questionnaire. Stress may also be induced when the researchers manipulate the subjects' environment - as when "emergencies" or fake "assaults" are staged to observe how passersby respond. More frequently, however, is the possibility of psychological harm when behavioral research involves an element of deception.  Invasion of privacy  is a risk of a somewhat different character. In the research context, it usually involves either covert observation or "participant" observation of behavior that the subjects consider private. 

The IRB must make two determinations: 

• is the invasion of privacy involved acceptable in light of the subjects' reasonable expectations of privacy in the situation under study; and 
• is the research question of sufficient importance to justify the intrusion? 

The IRB must also consider whether the research design could be modified so that the study can be conducted without invading the privacy of the subjects.  Breach of confidentiality  is sometimes confused with invasion of privacy, but it is really a different risk. Invasion of privacy concerns access to a person's body or behavior without consent; confidentiality of data concerns safeguarding information that has been given voluntarily by one person to another.  Some research requires the use of a subject's hospital, school, or employment records. Access to such records for legitimate research purposes is generally acceptable, as long as the researcher protects the confidentiality of that information. However, it is important to recognize that a breach of confidentiality may result in psychological harm to individuals (in the form of embarrassment, guilt, stress, and so forth) or in social harm (see below).  Social and Economic Harms:  Some invasions of privacy and breaches of confidentiality may result in embarrassment within one's business or social group, loss of employment, or criminal prosecution. Areas of particular sensitivity are information regarding alcohol or drug abuse, mental illness, illegal activities, and sexual behavior. Some social and behavioral research may yield information about individuals that could "label" or "stigmatize" the subjects. (e.g., as actual or potential delinquents or schizophrenics). Confidentiality safeguards must be strong in these instances.  Participation in research may result in additional actual costs to individuals. Any anticipated costs to research participants should be described to prospective subjects during the consent process. 

Ways to Minimize Risk 

• Provide complete information in the protocol regarding the experimental design and the scientific rationale underlying the proposed research, including the results of previous animal and human studies. 
• Assemble a research team with sufficient expertise and experience to conduct the research. 
• Ensure that the projected sample size is sufficient to yield useful results. 
• Collect data from standard-of-care procedures to avoid unnecessary risk, particularly for invasive or risky procedures (e.g., spinal taps, cardiac catheterization). 
• Incorporate adequate safeguards into the research design such as an appropriate data safety monitoring plan, the presence of trained personnel who can respond to emergencies, and procedures to protect the confidentiality of the data (e.g., encryption, codes, and passwords). 

Principal Investigators should conduct a detailed and appropriate literature review, and should detail: 

• all possible risks to the subject, whether physical, psychological, social, economic, legal, or 
• where the research may present a legal risk to subjects through a loss of confidentiality, address the need for a  Certificate of Confidentiality . 

If other methods of research present fewer risks, Principal Investigators should describe those, if any, that were considered and why they will not be used.  Any potential for discomfort associated with any test or procedure performed for research purposes should be noted. 

In general, risks to subjects must be minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk and whenever appropriate, by using data and procedures already being performed on the subjects for diagnostic or treatment purposes. 

For all research involving any risk of physical injury (including any adverse effect affecting the body, such as rashes and infections) these risks must be specified. If there are none, state: "There are no risks of physical injury.  However, if there are risks of physical injury, the protocol should state the potential injury, a careful estimate of its probability and severity, and its potential duration and the likelihood of its reversibility. 

There should be a statement as to whether these risks are presented by: 

• a procedure or modality performed or administered as part of standard care or 
• a procedure or modality performed or administered solely as a result of the subjects participation in the research protocol. 

Principal Investigators should specify: 

• quantities of body fluids or tissues (  e.g.  , volume of blood, urine, saliva, number of biopsies), 
• the time the subject will have to spend being tested, and 
• the duration of the study. 

Discussion of the risks should also include the risks of non-treatment.  If drugs or medical devices are being used which have known potential adverse side effects Principal Investigators should indicate if side effects are reversible.  Risks associated with a drug washout period, non-treatment or discontinuation of active drugs must be addressed by Principal Investigators.  Principal Investigators shall include a description of procedures (including confidentiality safeguards) for protecting against or minimizing injuries (physical, psychological and social) and provide an assessment of their likely effectiveness. There should be a clear statement about procedures for early detection of adverse effects and what steps, if any, will be taken to avoid injury to subjects, for example, the subject might be withdrawn from the study or a corrective drug might be administered. 

The Principal Investigator should indicate where subjects will be recruited (e.g.   in patient unit, walk in clinic, emergency room, ICU, or outside of UVA). The Principal Investigator should also note whether normal controls are to be used and, if applicable, recruitment methods (e.g. advertisements). . 

The IRB reviews the information contained in advertisements and other subject recruitment material and the mode of its communication. The IRB also reviews the format of any Internet information and the final copy of printed advertisements to evaluate the relative size of type used and other visual effects. 

IRB-HSR review and approval is required prior to initiating research involving health information. Investigators are not authorized to contact potential research subjects identified in reviews preparatory to research unless they are directly responsible for care of the potential subject and entitled to PHI as a result of that duty. All recruitment materials must be approved by the IRB prior to use.  Information about recruitment materials, IRB-HSR submission process, and templates are available on the IRB-HSR Website under  Subject Selection, Recruitment and Compensation .

Subject Compensation/Reimbursement 

It is not uncommon for subjects to be paid for their participation in research, especially in the early phases of investigational drug or device research or in behavioral and epidemiological research which require a significant time commitment on the part of the subject. The investigator should set forth the compensation plan in the protocol. Plans which call for the entire payment being made at the completion of the protocol may appear to be coercive. Subjects may also be reimbursed for out of pocket expenses related to participation (travel costs, parking expenses, child care, etc.) If such monetary compensation or reimbursement is to be offered, investigators should state the amount subjects are to receive. To view additional information on the difference between compensation and reimbursement click on “ More Information ”. Researchers should be aware of the  Compensation to Research Trial Participants Procedure  from the Office of the Vice President for Research. The procedure requires the researcher to provide justification if compensation cannot be done via the UVA Oracle System or if the researcher is unable to obtain tax information such as name, address, and Social Security number of recipient of compensation. For additional info see: Justification for use of an alternative method of compensation

Justification for not collecting the tax information . 

The Principal Investigator should name the professional staff who will be performing the study as sub-investigators, the research study coordinators, and other study support staff. Study staff must complete the UVA required CITI training program. Where specimens or data will be collected and stored, the Principal Investigator should indicate who will be responsible for storage, under what circumstances data or specimens will be released, what future types of research are anticipated using the specimens or data, and what steps will be taken to protect confidentiality (e.g. all identifiers stripped or, if coded, persons with access to code and location of code). Methods for protecting the security of information should be included. If the study is a Phase I or Phase II clinical trial and provides for a Data and Safety Management Board, those provisions should be included in the Data and Safety Monitoring Plan. 

In long term studies, study management issues that the Principal Investigator should consider are: the continuity of study personnel; availability of co-investigators; the timing of periodic review of data to assess trends; continuing training for data managers or study personnel to eliminate deviations from the protocol; and the investigator's plan, if any, to "re consent" subjects and obtain authorization over a number of years.

Confidentiality and Data Storage 

When appropriate, the subject should be assured that steps will be taken to assure confidentiality. The Principal Investigator should explain how subject confidentiality will be preserved, how data will be kept confidential and used for professional purposes, and whether data will be coded and where the data will be kept (  i.e.  , in locked files). This is particularly important in studies in which information will be recorded which, in the view of the subject, is sufficiently sensitive so that he/she would not wish persons other than the investigators to have access to it.  The protocol should also address any potential harm resulting. Whatever measures are taken to assure confidentiality should also be discussed in general terms in the consent form. Certain research may qualify for additional privacy protection in the form of a  Certificate of Confidentiality  (federal funding is not required).   Studies that are federally funded and that collect identifiable information are automatically granted a Certificate of Confidentiality by the NIH.   Investigators for studies not funded by the federal government may request a Certificate of Confidentiality to be issued by a Federal Agency when research is of a sensitive nature (e.g. involves information pertaining to illegal conduct or relating to the use of alcohol or drugs, sexual attitudes, preferences or practices, mental health, or information potentially damaging to the subject's financial standing, employability or reputation) and the additional protection is judged necessary to achieve the research objectives. 

The Principal Investigator should describe the types of analyses to be performed and evaluation techniques (endpoints, pharmacodynamic assessments, outcome measurements, etc.). If the study entails the collection of specimens, the analytical procedure to be followed should be presented and referenced (unless obvious). If a new technique that has not been documented in the literature is to be used, the Principal Investigator should describe the technique or include a statement about the method that will be developed. The Principal Investigator should indicate determinations of response to therapy. These may include laboratory assays, biopsies, bone marrow testing, absence of symptoms, or normal blood levels. The definition of partial response and failure should be included.  If the study is designed to evaluate behavior through the use of subjective or objective rating scales, or to study quality of life or activities of daily living, the method of evaluation should be explained with references.  The description of the analytical and statistical techniques should be as explicit as possible. All manipulations of the data should be explained, and the statistical methods to be used should be identified. Simple statements about an "appropriate analytical technique" and an "appropriate statistical test" are discouraged; they imply that the investigator has not fully planned the study. 

Bibliography 

A reasonable list of references directly related to the study should be included. 

When additional information is needed to support decisions made by the Principal Investigator, it should be included in an appendix. Typically, appendices include such information as height and weight tables, a description of analytical methodology, calculations, subject screening criteria, subjective and objective rating scales and any supportive literature. Any diagrams for new medical devices or brief reprints from journals might also prove useful.

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Guidelines for Writing a Human Research Protocol

I. objectives, ii. background and rationale, iii. procedures.

A complete description of the protocol must be submitted with initial applications for IRB or exempt review. The research protocol should provide the information needed for reviewers to determine that the regulatory and Human Research Protection Program (HRPP) policy requirements have been met. There is no required format or template; different sections and formatting may be used, provided the necessary information is included.

The purpose of the study (research questions and/or study objectives) should be clearly and succinctly stated. In experimental designs, objectives will be stated as hypotheses to be tested.

Summarize and synthesize the available research (including published data) to provide justification for the study. Evaluate prior research for relevance to the research question under study. When the proposed research is the first of its type to involve human participants, the results of relevant animal studies must be included. Discuss the anticipated results and potential pitfalls. Describe the significance of the research including potential benefits for individual subjects or society at large. Discuss how public health and social welfare might be enhanced.

The procedures should include the following:

Research Design

• Identify the research design that should be appropriate to answer the research question(s) under study.
• Describe the type of research proposed (e.g. experimental, correlational, survey, qualitative). 
• Describe the specific study design that will be used (e.g. pre-test /post-test control group design, cross-sectional design; prospective longitudinal cohort design; phase III double-blind randomized control group design).

Describe the Sampling Approach

• Include justification for sample size determination (for experimental designs).
• Identify the procedures that will be used to recruit, screen, and follow study volunteers.
• number of participants to be enrolled
• characteristics of participants to be included in and excluded from the research.

Measurement/Instrumentation

• Identify the variables of interest and study endpoints (where applicable).
• Justify measurement techniques selected.
• Provide validity and reliability data for selected measures.

Detailed Study Procedures

• Describe the selected methods sufficiently to justify the use of the approach for answering the defined research question.
• Describe methods for study data collection (include how to avoid/minimize subject risks) in detail so that IRB members can assess the potential study risks and benefits. 
• Include a timeline for participant evaluations and the duration of project participation in the project.
• Identify the plans for the proposed safeguards for participant confidentiality (plans for coding data and for securing written and electronic subject records).
• Indicate how long personal information will be stored once the study is completed.

Internal/External Validity

• Describe measures that have been taken to avoid study bias (consider the threats to internal/external validity).

Data Analysis Techniques

• Specify the analytic techniques the researcher will use to answer the study questions.
• Indicate the statistical procedures (e.g. specific descriptive or inferential tests) that will be used and why the procedures are appropriate.
• Specify the proposed analytic approaches for qualitative data.

2024 Courses Geneva Foundation for Medical Education and Research

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Application form - Brochure

Training course in research methodology, research protocol development and scientific writing 2024

Course coordinators Moazzam Ali (Department of Sexual and Reproductive Health & Research, World Health Organization) Jane Hirst (Nuffield Department of Women’s & Reproductive Health, University of Oxford) Karim Abawi (Geneva Foundation for Medical Education and Research)

Collaborating partners: Geneva Foundation for Medical Education and Research (GFMER), Oxford Maternal & Perinatal Health Institute (OMPHI) and the Department of Sexual and Reproductive Health & Research, World Health Organization (WHO)

The objective of this course is to provide knowledge and skills in research methodology, research protocol development and scientific writing to health professionals in sexual and reproductive health field. This course will enhance participants’ knowledge of research methodology and how to develop research protocols and improve their scientific writing.  

This course is divided into four thematic areas:

Literature search and referral to biomedical documents

The aim of conducting a literature search is to identify the most relevant sources related to a study topic in order to provide evidence, give background information, place research into a theoretical context and inform readers about similar research on the topic. A literature review is crucial for the credibility of a scientific paper and serves as an update of professional knowledge in a particular field of expertise.

Referencing is a standard way of citing the sources of information you have used and ideas that are not your intellectual property. It is important to verify citation and to allow readers to follow-up certain topics in further detail and locate the cited author’s original work.

Epidemiologic studies

This section provides basic knowledge on different epidemiological studies used to conduct research projects. It includes methods for observational (analytic & descriptive) studies, such as cross sectional, cohort, case-control and experimental studies like randomized trials. This section includes both quantitative and qualitative methods for conducting research as well as various data collection methods.

Research protocol development

This section provides practical instructions on how to develop a research protocol according to the WHO recommended format.

Scientific writing

This section provides instruction on scientific writing, such as article, report, presentation based on academic criteria.

Course topics

Week 1. Introduction: Research topic selection, research question and research problem statement

Week 2. Types of research, effective literature search and citing biomedical documents and sources

Week 3. Epidemiologic studies

Week 4. Systematic review and implementation research

Week 5. Sampling (sample size and sampling technique) and quantitative data collection

Week 6. Qualitative study design

Week 7. Research ethics and critical appraisal of research publication

Week 8. Research protocol development and scientific writing

Teaching-learning methods to be used in course

On each of the topic, the following items will be posted:

• A set of slides with accompanying talking points.
• Reference documents.
• Other audio-visual materials.

Teaching language

The teaching language of the course is English. Participants can develop their research protocols in English or French.

What is required of you?

For each module, participants must:

• Study the slides and talking points.
• Read all accompanying documents.
• Complete the short assignment / MCQs / interactive exercises, after going through the slide set and documents.

A personal coach will be assigned to each participant, whose role is to facilitate the course and serve as tutor.

Course validation and certificate

To validate the module and obtain the certificate, the participants are required to develop a research protocol relevant to their professional practice and under the guidance of their personal coach.

The successful participants will receive a certificate signed by the World Health Organization’s Department of Sexual and Reproductive Health and Research/Human Reproduction Programme, Oxford Maternal & Perinatal Health Institute and the Geneva Foundation for Medical Education and Research.

Course duration: 8 weeks

Course fee: USD 250

Important dates

Start date: 4 September 2024

End date: 29 October 2024

Application deadline: 21 August 2024

Payment deadline: 28 August 2024

Application

To apply for the course, you should submit the completed application form and send the required enclosures by email to the course email address ( [email protected] ).

Click to access the Application form

Please send the following documents by email to the course email address.

• A curriculum vitae, including sections on current and previous positions.
• A letter of motivation stating clearly your interests and reasons for applying to the Course (1 page / 500 words maximum).

Course email: [email protected] .

Geneva Foundation for Medical Education and Research Chemin de Beau-Soleil 12 1206 Geneva - Switzerland Email:  [email protected] Website:  https://www.gfmer.ch/

This paper is in the following e-collection/theme issue:

Published on 20.3.2024 in Vol 13 (2024)

Efficacy of Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT) in Individuals With Chronic Pain and Opioid Use Disorder: Protocol for a Randomized Clinical Trial of a Digital Cognitive Behavioral Treatment

Authors of this article:

• R Ross MacLean 1, 2 , PhD   ; 
• Brett Ankawi 2, 3 , PhD   ; 
• Mary A Driscoll 2, 3 , PhD   ; 
• Melissa A Gordon 2 , MFA   ; 
• Tami L Frankforter 2 , BA   ; 
• Charla Nich 2 , MS   ; 
• Sara K Szollosy 1 , MPH   ; 
• Jennifer M Loya 2 , PhD   ; 
• Larissa Brito 2 , BS   ; 
• Margaridha I P Ribeiro 2 , BA   ; 
• Sara N Edmond 2, 3 , PhD   ; 
• William C Becker 2, 3 , MD   ; 
• Steve Martino 1, 2 , PhD   ; 
• Mehmet Sofuoglu 1, 2 , MD, PhD   ; 
• Alicia A Heapy 2, 3 , PhD  

1 VA Connecticut Healthcare System, West Haven, CT, United States

2 School of Medicine, Yale University, New Haven, CT, United States

3 Pain Research, Informatics, Multimorbidities, and Education (PRIME) Health Services Research and Development Center of Innovation, VA Connecticut Healthcare System, West Haven, CT, United States

Corresponding Author:

R Ross MacLean, PhD

VA Connecticut Healthcare System

950 Campbell Ave

West Haven, CT, 06516

United States

Phone: 1 2039325711

Email: [email protected]

Background: Chronic pain is common among individuals with opioid use disorder (OUD) who are maintained on medications for OUD (MOUD; eg, buprenorphine or methadone). Chronic pain is associated with worse retention and higher levels of substance use. Treatment of individuals with chronic pain receiving MOUD can be challenging due to their increased clinical complexity. Given the acute and growing nature of the opioid crisis, MOUD is increasingly offered in a wide range of settings, where high-quality, clinician-delivered, empirically validated behavioral treatment for chronic pain may not be available. Therefore, digital treatments that support patient self-management of chronic pain and OUD have the potential for wider implementation to fill this gap.

Objective: This study aims to evaluate the efficacy of Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT), an interactive digital treatment program with asynchronous coach feedback, compared to treatment as usual (TAU) in individuals with chronic pain and OUD receiving MOUD.

Methods: Adult participants (n=160) receiving MOUD and reporting bothersome or high-impact chronic pain will be recruited from outpatient opioid treatment programs in Connecticut (United States) and randomized 1:1 to either IMPACT+TAU or TAU only. Participants randomized to IMPACT+TAU will complete an interactive digital treatment that includes 9 modules promoting training in pain and addiction coping skills and a progressive walking program. The program is augmented with a weekly personalized voice message from a trained coach based on daily participant-reported pain intensity and interference, craving to use opioids, sleep quality, daily steps, pain self-efficacy, MOUD adherence, and engagement with IMPACT collected through digital surveys. Outcomes will be assessed at 3, 6, and 9 months post randomization. The primary outcome is MOUD retention at 3 months post randomization (ie, post treatment). Secondary outcomes include pain interference, physical functioning, MOUD adherence, substance use, craving, pain intensity, sleep disturbance, pain catastrophizing, and pain self-efficacy. Semistructured qualitative interviews with study participants (n=34) randomized to IMPACT (completers and noncompleters) will be conducted to evaluate the usability and quality of the program and its outcomes.

Results: The study has received institutional review board approval and began recruitment at 1 site in July 2022. Recruitment at a second site started in January 2023, with a third and final site anticipated to begin recruitment in January 2024. Data collection is expected to continue through June 2025.

Conclusions: Establishing efficacy for a digital treatment for addiction and chronic pain that can be integrated into MOUD clinics will provide options for individuals with OUD, which reduce barriers to behavioral treatment. Participant feedback on the intervention will inform updates or modifications to improve engagement and efficacy.

Trial Registration: ClinicalTrials.gov NCT05204576; https://clinicaltrials.gov/ct2/show/NCT05204576

International Registered Report Identifier (IRRID): DERR1-10.2196/54342

Introduction

Despite increased attention from the media, policy makers, researchers, and clinicians, the opioid epidemic in the United States remains a significant public health crisis. Approximately 107,000 US adults died by drug overdose in 2021, with increases in every age group and an overall age-adjusted 14% increase from the previous year [ 1 ]. An estimated two-thirds of overdose deaths involved synthetic opioids other than methadone (eg, illicitly manufactured fentanyl) [ 2 ]. Medications for opioid use disorder (MOUD), including buprenorphine and methadone, are protective against mortality in individuals with opioid use disorder (OUD) [ 3 , 4 ], reducing overdose death and all-cause death by 8 and 2.5 times, respectively [ 5 ]. Furthermore, longer retention in MOUD is associated with a continued reduction in mortality [ 5 ]. Retention of at least 6 months, and often longer, is needed to obtain full benefits, including a return to work and improvements in fulfilling family and social responsibilities [ 6 , 7 ]. Despite these benefits, only 36% of individuals who initiate are retained in MOUD for 6 months, with retention rates falling to 22% at 1 year [ 8 ]. Therefore, developing interventions that support MOUD retention and address co-occurring conditions that interfere with retention is essential to enabling people with OUD to obtain the full benefits of MOUD treatment.

Role of Pain in the Development of OUD

One condition that commonly co-occurs with OUD is chronic pain, frequently defined as pain that persists for 3 months or more. Chronic pain is a widespread affliction in the United States, affecting approximately 1 in 5 adults [ 9 ], and is more common among people with OUD. A large study of electronic health records revealed that 64.4% of individuals with OUD also had a chronic pain condition [ 10 ]. Chronic pain can be a pathway to OUD, with 4 out of 5 individuals who use heroin reporting their initial exposure to opioids was through a prescription for pain treatment [ 11 , 12 ]. It is a common misconception, even among addiction providers, that methadone and buprenorphine provide adequate pain treatment for individuals with OUD [ 13 ]. Unsurprisingly, chronic pain typically persists when MOUD is the sole treatment modality. Among individuals enrolled in methadone or buprenorphine treatment, estimates of chronic pain range from 40% to 80% [ 14 - 17 ].

Chronic Pain Negatively Affects MOUD Outcomes

The presence of chronic pain may undermine the effectiveness of MOUD. A large randomized, controlled multisite trial of buprenorphine in individuals with OUD found greater pain severity significantly increased the odds of opioid use in the following week [ 18 ]. Follow-up analyses revealed that variability or volatility in pain intensity was associated with craving, relapse to opioid use, and poorer outcomes [ 18 , 19 ]. Furthermore, the experience of pain has been cited as the most common reason for returning to use while engaged in MOUD [ 20 ]. Finally, few people receiving MOUD receive adequate evidence-based pain care; this has been recognized as an important gap in the treatment of comorbid OUD and chronic pain [ 15 , 21 - 24 ].

Individuals with chronic pain receiving MOUD, compared to those without chronic pain, have higher rates of psychiatric and medical comorbidities, including sleep disturbances, and higher rates of health service use and levels of functional impairment [ 21 , 25 - 27 ]. Comprehensive treatment for individuals with concurrent chronic pain and OUD may require interventions that address mood, anxiety, sleep, and functional difficulties to maximize OUD treatment outcomes, such as MOUD retention. That is, chronic pain with OUD does not necessarily indicate more severe OUD; rather, it represents a concurrent disorder that may have a different clinical course and treatment response than OUD alone [ 22 , 28 ]. Accordingly, treatments should consider the relationship between chronic pain and opioid use while addressing barriers to engagement in resource-limited MOUD clinics.

Cognitive Behavioral Therapy Is an Evidence-Based Treatment for Both Chronic Pain and Substance Use, but it has Limited Accessibility

Cognitive behavioral therapy (CBT) has a strong evidence base for the treatment of chronic pain [ 29 ] and substance use disorders [ 30 - 33 ]. CBT for chronic pain has been recommended by the Centers for Disease Control and Prevention and the National Institutes of Health (NIH) as a first-line treatment to reduce pain and improve function [ 34 , 35 ]. Although MOUD clinicians report interest in nonpharmacologic pain treatment, very few report confidence in their own ability to address chronic pain [ 36 ]. Similar to chronic pain, CBT for substance use disorders has been shown to have moderate effects on reducing substance use, promoting abstinence from substances, increasing the use of coping skills, and promoting other positive psychosocial outcomes in individuals with addiction [ 37 ]. Engagement in CBT for substance use disorder is a mainstay in outpatient and inpatient treatment, but, akin to CBT for chronic pain, implementing CBT with high fidelity is challenging due to the lack of trained clinicians in the setting [ 38 , 39 ]. For these reasons, offering adjunctive CBT in MOUD clinics has resulted in mixed findings [ 40 - 42 ]. Taken together, there is a critical gap in treatment where individuals with OUD receiving MOUD have few options for addiction or pain treatment. Accordingly, there has been a recent call to develop rigorous, evidence-based digital treatments for individuals with OUD, which can be integrated into MOUD clinical settings [ 43 ].

Development of Integrating the Management of Pain and Addiction via Collaborative Treatment

Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT) combines 2 evidence-based digital CBT treatments: Computer-Based Treatment for Cognitive Behavioral Therapy (CBT4CBT) and Cooperative Pain Education and Self-Management (COPES) treatment programs ( Figure 1 ). CBT4CBT is a web-based program designed to improve behavioral and cognitive coping skills that have been evaluated in a range of substance use disorders [ 44 - 47 ], including 2 trials indicating its effectiveness and durability for individuals with OUD on methadone maintenance [ 48 , 49 ] and office-based buprenorphine maintenance [ 50 ]. COPES is an interactive voice response–based treatment for chronic pain that is delivered asynchronously through telephone [ 51 ] and has been shown to be similarly effective in reducing pain intensity and improving physical functioning, sleep quality, and quality of life as real-time CBT with a therapist [ 52 ]. IMPACT was designed to provide an easily accessible, standardized evidence-based intervention for those with OUD and chronic pain that could ultimately be easily integrated into MOUD clinic settings.

This study was funded by the National Center for Complementary and Integrative Health’s Behavioral Research to Improve Medication-Based Treatment (BRIM) program. The goal of BRIM, funded by NIH’s Helping to End Addiction Long-Term (HEAL) initiative, is to examine the role of behavioral interventions in improving the outcomes of MOUD, particularly MOUD access and retention. The R61/R33 award described here consists of 2 phases: a preparatory R61 phase used to develop the intervention and identify recruiting sites and the R33 clinical trial that is the focus of this protocol.

Study Objectives

The study is designed to evaluate the efficacy of IMPACT along with treatment as usual (IMPACT+TAU) versus TAU only at 3 months post randomization (primary end point). The primary OUD outcome is verified retention in MOUD treatment, defined as enrollment in MOUD (ie, yes or no), with evidence of MOUD use in the week before the 3-month time point. Secondary treatment outcomes will include pain interference, physical functioning, MOUD adherence, substance use, craving, pain intensity, sleep disturbance, pain catastrophizing, and pain self-efficacy at 3 months post randomization. The secondary aim is to evaluate the durability of effects for MOUD retention at 6 and 9 months post randomization. The tertiary aim is to examine treatment usability and quality through qualitative interviews with individuals randomized to IMPACT.

Study Design

This is a randomized clinical trial comparing the efficacy of IMPACT+TAU relative to TAU among individuals enrolled in MOUD treatment who have chronic pain. Outcomes will be assessed at baseline, 3, 6, and 9 months post randomization ( Figure 2 ).

Study Population and Setting

Participants will be 160 individuals with chronic pain receiving MOUD (methadone or buprenorphine) at participating outpatient opioid treatment program (OTP) sites located in Bridgeport, Danbury, and Waterbury (Connecticut).

Ethical Considerations

The study was approved by the Yale University Institutional Review Board on September 4, 2019 (2000026276). Subsequent modifications were implemented to add posttreatment qualitative interviews to assess treatment satisfaction and usability, as well as to refine recruitment materials and add recruitment sites. The study was subsequently approved by the Veterans Affairs Connecticut Human Subjects Subcommittee because, although not enrolling Veteran Affairs patients, several study staff are employees of the Department of Veterans Affairs.

Study Population

Textbox 1 contains inclusion and exclusion criteria for patients.

Inclusion criteria

• Be 18 years of age or older
• Meet theDiagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for opioid use disorder and be enrolled in methadone or buprenorphine treatment at the participating medications for opioid use disorder (MOUD) clinic
• Receiving a stable (ie, unchanged in 2 weeks) dose of MOUD as judged by the prescribing clinician
• Report bothersome or high-impact chronic pain defined by the Graded Chronic Pain Scale–Revised
• Have a self-reported ability to walk at least 1 block

Exclusion criteria

• Inability to read, write, and speak English at a third-grade level
• Untreated or inadequately treated bipolar or psychotic disorder or current suicide risk for the previous 2 weeks before screening (identified using baseline measures)
• Life-threatening health conditions that would impede participation (eg, end-stage renal failure, malignant cancer requiring chemotherapy)
• Planned surgical treatment related to pain
• Pending legal action or planned relocation that would interfere with participation

Justification for Criteria

Participants will be adults receiving a stable dose of MOUD because, until the dose is stable, pain ratings may fluctuate and obscure the intervention’s effect. We require bothersome or high-impact chronic pain (ie, moderate to severe pain that limits life and work activities on most days or every day in the past 3 months) because, compared to individuals with mild chronic pain, it is more commonly associated with negative health indicators addressed in cognitive behavioral treatment for chronic pain (eg, negative pain coping beliefs, pain interference, and psychological distress) [ 53 ]. IMPACT contains a progressive walking program; therefore, to ensure participant safety, participants must be able to walk at least 1 block. Individuals with low literacy (ie, <third grade) or medical or psychiatric diagnoses that would interfere with their ability to meaningfully participate in the IMPACT treatment, such as severe mental health conditions (eg, unmedicated or untreated bipolar or psychotic disorder, current suicide risk, or diagnoses requiring palliative or end-of-life care), are excluded. Individuals with circumstances that may predictably interfere with participation (eg, legal actions with imminent incarceration) or produce large changes in pain (pain-related surgeries) will be excluded. Women of childbearing age will be included, as there is no contraindication for CBT for pain or substance use disorder for pregnant women. Participants who do not have a digital device (eg, smartphone or tablet) for participating in IMPACT will be supplied with one for the duration of the study.

Recruitment, Screening, and Consent Procedures

Study recruitment occurs through clinician referral of interested patients and patient self-referral in response to informational study materials posted in patient care areas at the recruiting sites. Site clinicians receive information about the study and eligibility criteria through research staff presentations and study informational material provided at clinical staff meetings. Self- and clinician-referred individuals are screened by a study research assistant and, if eligible, invited to consent and complete a baseline assessment. Procedures are conducted in a quiet and private office space provided by the OTP clinic to the research team. The research assistant and the participant discuss the consent document, and potential participants are provided an opportunity to ask questions and time to consider their decision to participate. A comprehension quiz is given to ensure the participant has an adequate understanding of the study, and a copy of the consent form is given to the participant. After consent, the research assistant assigns a unique study ID code and administers baseline measures on a study laptop using the REDCap (Research Electronic Data Capture) software platform.

Randomization and Masking

Following the baseline assessment, participants are randomized 1:1 to IMPACT+TAU or TAU (control) using urn randomization [ 54 ] balanced by demographic variables (self-reported gender identification and race or ethnicity [combination of ethnicity and racial identity]), as well as likely prognostic variables (severity of OUD as mild, moderate, or severe based on the DSM-5 [ Diagnostic and Statistical Manual of Mental Disorders {Fifth Edition} OUD symptom count), buprenorphine versus methadone treatment, and length of MOUD treatment (<6 months, 6-12 months, and >12 months). Allocation is masked using a Microsoft Access (Microsoft Corp) program that our group has developed and implemented successfully in multiple previous trials [ 55 - 58 ]. Participants randomized to IMPACT+TAU are provided with a unique username and password to access the IMPACT website. To facilitate their participation in the walking portion of the treatment, participants are given a pedometer and a brief demonstration of its use. Study staff measure each participant’s stride length and calibrate the pedometer accordingly. The research assistant then guides the participants through the first IMPACT module to ensure they are comfortable using the program and answer any questions they might have.

Interventions

Participants allocated to IMPACT+TAU receive standard MOUD treatment (ie, TAU) along with access to IMPACT for 12 weeks. IMPACT is a self-directed, 9-module digital treatment program with weekly personalized feedback messages from a trained masters- or doctoral-level coach under the supervision of a clinical psychologist. Participants are asked to complete 1 module per week using a study laptop that is available in the MOUD clinic or outside of the clinic using their own web-enabled device (eg, at home). We hope to maximize treatment adherence and engagement by providing multiple ways of accessing the IMPACT program [ 50 ]. The IMPACT program passively tracks individual behaviors to capture engagement (ie, number of logins, access to each module and component, time spent using the program, and digital survey completion). Module topics are shown in Figure 3 . For each module, participants are asked to practice a specific skill that corresponds with the topic for that week. After indicating a baseline average number of steps during their first week of completing the daily survey, participants are provided with a daily step goal by their coach during the weekly feedback message. The goal is to increase their daily steps by 10% of the average daily step count reported in the previous week. All modules include a narrated introduction of the skill, video vignettes of characters in challenging situations and using skills, interactive practice exercises and weekly skill practice goals, and a quiz to evaluate the understanding of the module content. The IMPACT dashboard landing page displays personalized information for each participant, including a badge for each completed module, stars for completion of practice exercises, weekly averages of daily steps and step goals in graphical form, and a link to weekly coach messages.

Participants receive links to daily digital surveys through MMS text messages on their mobile phone at a participant-selected time for the duration of treatment. Surveys assess pain intensity, pain interference, pedometer-measured step counts, sleep quality, sleep duration, craving to use opioids, self-efficacy, MOUD adherence, and questions regarding the practice of the treatment skills. Based on our previous work, digital surveys are estimated to take no longer than 2 minutes to complete. Coaches review summaries of the daily survey data through a web portal that displays survey responses from the past week (as weekly averages or individual days). The coach records an audio message based on the participant-provided responses to the current week’s surveys, as well as previous weeks, that is uploaded to the participant’s IMPACT dashboard. The coach’s message provides reinforcement of skill practice and goal attainment and highlights associations between participants’ daily responses and trends in weekly averages over the course of treatment. Coaches receive training in message preparation and attend weekly supervision with a clinical psychologist. Participants are not able to directly respond to the coach’s feedback through the program but are able to indirectly communicate with the coach by leaving a message with the research assistant during their weekly clinic visit, who can relay the message to the coaches.

TAU (Control)

Participants in both conditions receive TAU for the buprenorphine and methadone programs at participating MOUD clinics, which includes regular medication management by the clinic physician and regular individual and group counseling sessions delivered on-site by counselors employed at participating MOUD clinics. Participants randomized to IMPACT+TAU and TAU will receive MOUD dosing as indicated by their OTP clinician in conjunction with regular meetings as dictated by their treatment plan. Both groups are free to access any OTP clinic resources, including prescriptive services for mental health issues, group treatment, and individual counseling as offered at each recruitment site.

Assessment Visits

The study includes a baseline visit followed by brief weekly visits during treatment (up to 12 weeks) and a 3-, 6-, and 9-month postrandomization assessment visit. Neither participants nor research assistants are blinded to group assignments. However, outcome measures are obtained through self-report using REDCap digital assessments, and MOUD retention will be verified with MOUD clinic records, limiting the potential for bias. Participants complete the baseline, weekly visit, posttreatment, and follow-up measures at their outpatient MOUD clinic to facilitate the collection of a urine sample for urine toxicology analysis ( Table 1 ). After baseline, if in-person attendance is not possible, study measures may be completed remotely. Remote participation is facilitated by the use of digital data collection, videoconferencing, or the telephone.

a MOUD: medications for opioid use disorder.

b MINI: Mini-International Neuropsychiatric Interview.

c PROMIS: Patient Reported Outcomes Measurement Information System.

d Adherence will be assessed with the Timeline Followback for daily MOUD use for the previous week, clinic dispensing records, and urine toxicology screen for buprenorphine or methadone collected at each weekly assessment visit.

e NRS: Numerical Rating Scale.

f PHQ-4: Patient Health Questionnaire-4.

g IMPACT: Integrating the Management of Pain and Addiction via Collaborative Treatment.

h TAU: treatment as usual.

Primary Outcome Measure (Retention in MOUD)

Retention is defined as dichotomous enrollment in MOUD (ie, yes or no), with evidence of MOUD uptake in the week before the 3- (primary), 6-, and 9-month time points. Using data from the 7 days before the 3-month time point, dichotomous enrollment in MOUD services will be verified by clinic records and evidence of MOUD compliance will be assessed using clinic records and self-report. When these sources disagree, clinic records will be used to determine compliance. Retention will be a binary outcome, with 1=retained (conditions met) and 0=not retained.

Secondary Treatment Outcome Measures

We will also collect OUD (ie, MOUD adherence, craving, and substance use) and pain (ie, pain interference, physical functioning, pain intensity, sleep disturbance, pain catastrophizing, and pain self-efficacy) secondary outcome measures. These outcomes evaluate other important treatment effects that have an evidence base in OUD and chronic pain treatment studies and will provide a more detailed assessment of possible treatment outcomes. Outcome measures are detailed in Table 1 .

Other Measures

To better characterize other treatment effects, we will also evaluate general psychological symptoms, depression symptoms, anxiety symptoms, OTP treatment use and cost, cold pressor task (pain threshold), and digital treatment engagement (only participants randomized to IMPACT+TAU).

Data Sharing

Data collected during baseline, post treatment, and follow-up visits will be made available in compliance with the HEAL Public Access and Data Sharing policy. The study is registered in ClinicalTrials.gov and is in the process of being registered in the HEAL Data Platform. Once data collection is complete, 1 master data file will be created that includes all variables necessary to address the primary study aims and hypotheses. All analyses will be performed using the master data file. The final master data set will then be submitted to the appropriate HEAL-approved repository. All data will be deidentified before submission using procedures that are in compliance with the HIPAA (Health Insurance Portability and Accountability Act), the Yale Human Investigation Committee, and NIH standards.

Qualitative Interviews

Among those randomized to IMPACT+TAU, individual interviews (N=34) will be conducted at 3-month follow-up with a sample of completers (n=17) and noncompleters (n=17). This sample size should be sufficient to achieve saturation on interview themes; however, if saturation is not reached, additional participants will be interviewed until saturation is attained [ 72 ]. Completers will be defined as any participant that engages in 7-9 IMPACT modules. Noncompleters will be defined as any participant who completed between 1 and 4 IMPACT modules. Interviews will take place on the internet or in person, be digitally recorded, and be transcribed. All respondents will be asked a series of open-ended questions to probe participant experiences with IMPACT, including barriers or facilitators to engagement and how IMPACT influenced their ability to manage pain and OUD. Semistructured questions will elicit feedback on various features of the intervention, including the various module topics ( Figure 3 ), the walking component, impressions of the weekly personalized feedback, the IMPACT platform, study outcomes, daily surveys, and combined emphasis on pain or OUD.

Data Analyses

Quantitative data analysis.

Data will be reported for each treatment arm and overall at all time points in the study. Summary descriptions of recruitment rates, attrition, daily survey completion, and treatment outcomes will be calculated. The baseline demographic characteristics of both groups will be summarized.

We will perform a true intent-to-treat analysis of the primary MOUD retention outcome that will include all randomized participants and use logistic regression models to assess differences in MOUD retention by treatment condition at the 3-month time point. MOUD type (ie, buprenorphine or methadone) will be specified as a covariate. Similarly, the logistic regression model will be used to assess differences in MOUD retention by treatment condition at each follow-up time point (ie, 6 and 9 months post randomization).

In addition to retention, we will run secondary analyses to evaluate differences in several OUD (ie, MOUD adherence, craving, and substance use) and pain (ie, pain interference, physical functioning, pain intensity, sleep disturbance, pain catastrophizing, and pain self-efficacy) measures by treatment condition and by time using multilevel longitudinal models with MOUD type (ie, buprenorphine or methadone) specified as a between-person covariate.

Qualitative Data Analysis

Analysis of qualitative data will be conducted using Atlas.ti, a qualitative software program allowing fluid interaction of data across types or sources [ 73 ]. A qualitative-descriptive approach is suitable when information is needed to develop, summarize, or refine an intervention [ 74 ]. A constant comparative approach with sequential analysis will be used to reach a thematic consensus. Memos, field notes, and debriefing notes after each interview will also be incorporated into the analysis [ 75 ]. Each transcript will first be read in its entirety and then coded, proceeding from line-by-line in vivo codes to more broad codes and themes, comparing data across participants [ 75 ]. Coding will be completed independently by 2 researchers and compared, and final themes will be arrived at through consensus. Findings will be summarized and presented in tables. It is expected that the collected data will reflect mechanisms underlying engagement and participant perspectives of IMPACT.

The funding for the clinical trial component of the study (phase 2) was obtained in June 2022, and the trial study protocol that included changes from phase 1 was approved by the institutional review board in January 2022. Enrollment began on July 15, 2022, at a single outpatient clinic; a second outpatient clinic was added on March 6, 2023; and a third site is expected in January 2024. Enrollment is expected to continue until June 2024. Final data are expected to be collected in March to May 2025, and the primary results of the study are expected to be published in March to May 2026.

Summary of Study Significance

Given the prevalence of OUD and the increased mortality by overdose, the provision of MOUD and support for retention in MOUD are critical. Only a third of individuals receiving MOUD are retained in treatment after 6 months. Clearly, many people receiving MOUD require additional support to remain in treatment and attain its full benefit. Chronic pain, a common co-occurring condition among those receiving MOUD, interferes with MOUD retention and diminishes functioning and quality of life. An asynchronous digital integrated treatment for addiction and chronic pain, such as IMPACT, holds promise to increase access to evidence-based behavioral treatment in MOUD clinical care. IMPACT is designed to be accessible, low-burden, and easily integrated into MOUD clinics despite their limited resources.

Benefits of Daily Surveys

Importantly, IMPACT collects individual responses through daily surveys that are used to generate weekly personalized feedback for participants. These data are the foundation of personalized coach feedback that may enhance engagement with treatment, which has been suggested in previous reviews [ 76 ] and yield relatively fine-grained data on patient reports of pain and pain interference, craving to use opioids, sleep problems, and physical activity for a comparatively large sample of individuals enrolled in MOUD. Daily ratings of pain and pain fluctuations in this population are unique, and the data generated will be critical in addressing key gaps in the literature, including understanding fluctuations in relationships between pain and pain interference, drug craving, treatment retention, sleep, and functioning in this population. These data may provide actionable information for further treatment refinement.

Benefit of Digital Interventions in the MOUD Setting

An integrated, digital intervention offers 2 particularly attractive benefits in the MOUD setting: a means to both (1) obtain treatment in a less stigmatizing manner and (2) provide treatment with high fidelity to evidence-based protocols without adding staff. Individuals receiving MOUD report high levels of stigma that can significantly impact the course of treatment [ 77 - 79 ]. Increased stigma is a primary barrier to engaging in MOUD treatment and is present even among addiction providers. In a recent qualitative study of MOUD providers, the perception of psychosocial interventions is mixed, with some providers suggesting that MOUD undermines the effectiveness of behavioral treatment while others argue that any provision of behavioral treatment is not a necessary component of MOUD treatment [ 80 ]. Furthermore, integrating evidence-based psychotherapies, such as CBT, into MOUD clinical care has been met with mixed results [ 81 - 83 ]. Some researchers have posited that the inconsistent findings are likely related to methodological flaws in previous research, including low fidelity and an inadequate control group [ 42 ]. IMPACT treatment materials can be delivered with a high degree of fidelity and consistency, effectively removing a lack of fidelity as a potential driver of outcomes in this study. The patient demands of MOUD clinical care often preclude trained providers from delivering behavioral treatment [ 84 ]. Technology-based and digital interventions, such as IMPACT, can address these barriers by offering treatment with high fidelity that can be completed outside the clinic, further reducing the possible stigma of discussing problems related to addiction and pain in MOUD settings.

Limitations

There are several limitations to the current protocol. First, as is common in behavioral intervention trials, participants will be unblinded to the condition once randomized. However, all participants and researchers will be blind to the condition when completing baseline structured interview measures. The primary outcome is based on objective measures and clinic attendance and, therefore, is less vulnerable to biases associated with being unblinded. Other treatment outcomes are collected through self-reported responses in REDCap, which also limits the potential for bias. There is also no attention control for IMPACT. We chose to use TAU as the control condition to maximize our ability to determine the efficacy of adding a digital treatment to the existing gold standard treatment (ie, MOUD). Next, participants randomized to IMPACT may not complete all daily surveys, resulting in missing data. While we expect that participants will miss surveys, completing the surveys benefits participants because they provide personalized feedback; and even 1-2 surveys per week can provide insight for weekly coach feedback. Additionally, previous research on COPES has shown high survey completion [ 85 ], which is consistent with findings from other asynchronous chronic pain interventions using daily surveys [ 86 ]. Finally, participants in both groups may receive other pain and addiction treatments both within and outside their MOUD clinic. We will inquire about additional treatment at weekly visits during treatment to account for any effects that could be attributed to other interventions.

Conclusions

Access to behavioral treatment for individuals with OUD and chronic pain is a critical gap in MOUD care. Offering access to a combined pain and addiction treatment may help retain individuals in MOUD while improving clinical outcomes for people who otherwise may not receive treatment. Digital treatments are especially well-suited to MOUD treatment settings because they reduce stigma and provide access to high fidelity, evidence-based behavioral treatment.

Acknowledgments

We would like to respectfully acknowledge the late Kathy M Carroll, PhD, for her contributions to the design of this study before her untimely passing in late 2020. Dr Carroll’s brilliance was only surpassed by her unwavering commitment to increasing the accessibility of evidence-based treatment to improve the lives of individuals with substance use disorders. With this project, we continue her legacy with the same compassion and empathy that defined her professional and personal life. This research is supported by R61/33AT010619 (Heapy). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the National Center for Complementary and Integrative Health, or the Department of Veterans Affairs.

Data Availability

Deidentified data sets generated during the course of this study will be made available on the Helping to End Addiction Long-Term (HEAL) Data Platform through a HEAL-approved repository.

Authors' Contributions

AAH, MAG, TLF, CN, WCB, SM, and MS contributed to the conceptualization of the study. AAH, RRM, BA, MAG, TLF, CN, SNE, WCB, SM, and MS contributed to the study design, development of the Integrating the Management of Pain and Addiction via Collaborative Treatment (IMPACT) program during the R61 phase, and clinical trial during the R33 phase. RRM wrote the initial draft, and AAH, SKS, JML, LB, MIPR, MAG, and MAD provided critical edits. All authors read and approved the final manuscript.

Conflicts of Interest

None declared.

Peer-viewer report from the National Centre for National Center for Complementary and Integrative Health (NCCIH).

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Abbreviations

Edited by A Mavragani; The proposal for this study was peer reviewed by the National Center for Complementary and Integrative Health (NCCIH). See the Multimedia Appendix for the peer-review report; submitted 08.11.23; accepted 25.01.24; published 20.03.24.

©R Ross MacLean, Brett Ankawi, Mary A Driscoll, Melissa A Gordon, Tami L Frankforter, Charla Nich, Sara K Szollosy, Jennifer M Loya, Larissa Brito, Margaridha I P Ribeiro, Sara N Edmond, William C Becker, Steve Martino, Mehmet Sofuoglu, Alicia A Heapy. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.03.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.

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‘Dramatic’ inroads against aggressive brain cancer

Cutting-edge therapy shrinks tumors in early glioblastoma trial

Haley Bridger

Mass General Communications

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment.

In a paper published Wednesday in The New England Journal of Medicine, researchers from Mass General Cancer Center shared the results for the first three patient cases from a Phase 1 clinical trial evaluating a new approach to CAR-T  therapy for glioblastoma.

Just days after a single treatment, patients experienced dramatic reductions in their tumors, with one patient achieving near-complete tumor regression. In time, the researchers observed tumor progression in these patients, but given the strategy’s promising preliminary results, the team will pursue strategies to extend the durability of response.

Left: MRI in Participant 3 before infusion. Right: After infusion on day five.

Image courtesy of The New England Journal of Medicine

“This is a story of bench-to-bedside therapy, with a novel cell therapy designed in the laboratories of Massachusetts General Hospital and translated for patient use within five years, to meet an urgent need,” said co-author Bryan Choi , a neurosurgeon at Harvard-affiliated Mass General and an assistant professor at Harvard Medical School. “The CAR-T platform has revolutionized how we think about treating patients with cancer, but solid tumors like glioblastoma have remained challenging to treat because not all cancer cells are exactly alike and cells within the tumor vary. Our approach combines two forms of therapy, allowing us to treat glioblastoma in a broader, potentially more effective way.”

The new approach is a result of years of collaboration and innovation springing from the lab of Marcela Maus , director of the Cellular Immunotherapy Program and an associate professor at the Medical School. Maus’ lab has set up a team of collaborating scientists and expert personnel to rapidly bring next-generation genetically modified T cells from the bench to clinical trials in patients with cancer.

“We’ve made an investment in developing the team to enable translation of our innovations in immunotherapy from our lab to the clinic, to transform care for patients with cancer,” said Maus. “These results are exciting, but they are also just the beginning — they tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease. We haven’t cured patients yet, but that is our audacious goal.”

CAR-T (chimeric antigen receptor T-cell) therapy works by using a patient’s own cells to fight cancer — it is known as the most personalized way to treat the disease. A patient’s cells are extracted, modified to produce proteins on their surface called chimeric antigen receptors, and then injected back into the body to target the tumor directly. Cells used in this study were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.

CAR-T therapies have been approved for the treatment of blood cancers, but the therapy’s use for solid tumors is limited. Solid tumors contain mixed populations of cells, allowing some malignant cells to continue to evade the immune system’s detection even after treatment with CAR-T. Maus’ team is working to overcome this challenge by combining two previously separate strategies: CAR-T and bispecific antibodies, known as T-cell engaging antibody molecules. The version of CAR-TEAM for glioblastoma is designed to be directly injected into a patient’s brain.

In the new study, the three patients’ T cells were collected and transformed into the new version of CAR-TEAM cells, which were then infused back into each patient. Patients were monitored for toxicity throughout the duration of the study. All patients had been treated with standard-of-care radiation and temozolomide chemotherapy and were enrolled in the trial after disease recurrence.

• A 74-year-old man had his tumor regress rapidly but transiently after a single infusion of the new CAR-TEAM cells.
• A 72-year-old man was treated with a single infusion of CAR-TEAM cells. Two days after receiving the cells, an MRI showed a decrease in the tumor’s size by 18 percent. By day 69, the tumor had decreased by 60 percent, and the response was sustained for more than six months.
• A 57-year-old woman was treated with CAR-TEAM cells. An MRI five days after the infusion showed near-complete tumor regression.

The authors note that despite the remarkable responses among the first three patients, they observed eventual tumor progression in all the cases, though in one case, there was no progression for over six months. Progression corresponded in part with the limited persistence of the CAR-TEAM cells over the weeks following infusion. As a next step, the team is considering serial infusions or preconditioning with chemotherapy to prolong the response.

“We report a dramatic and rapid response in these three patients. Our work to date shows signs that we are making progress, but there is more to do,” said co-author Elizabeth Gerstner, a Mass General neuro-oncologist.

In addition to Choi, Maus, and Gerstner, other authors are Matthew J. Frigault, Mark B. Leick. Christopher W. Mount, Leonora Balaj, Sarah Nikiforow, Bob S. Carter, William T. Curry, and Kathleen Gallagher.

The study was supported in part by the National Gene Vector Biorepository at Indiana University, which is funded under a National Cancer Institute contract.

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Center for Injury Research and Policy

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Staff Feature: Himani Byregowda

Himani Byregowda is a Senior Research Data Analyst at the Bloomberg School of Public Health (BSPH), Department of Mental Health, and a Teaching Fellow with the BSPH Center for Injury Research and Policy. 

How did you get into the field of injury prevention?   It was through my work on the Maryland Overdose Data Collaborative, where we evaluated overdose prevention programs in Maryland. During my previous training as a Dental Surgeon in India, I came across patients who had oral carcinomas attributable to smoking and drug use. Witnessing their pain and suffering was devastating and prompted me to embark on a career dedicated to substance use prevention.

Tell us about an active project that you are currently working on.   I’m working with Drs. Ramin Mojtabai and Rosa Crum on examining the effect of psychiatric comorbidity on substance use disorder (SUD) outcomes. Often individuals with SUDs also experience psychological distress or meet the criteria for common mood and anxiety disorders. We are using data from 20 NIDA-sponsored randomized control trials to enhance our understanding of the relationship between psychiatric comorbidity and SUD treatment outcomes. I’m hoping our findings will help improve the care of patients with co-occurring mental and substance use disorders and optimize the effectiveness of SUD treatments.

What is your favorite part about being affiliated with the Injury Center? I currently serve as the Teaching Fellow for the Graduate Seminar in Injury Research and Policy, a weekly series held every Monday at noon. I enjoy learning about different injury-related topics each week and connecting with researchers and students from across the globe!

If you could have lunch with any celebrity, who would you meet and what would you talk about? I think it would be Ons Jabeur, she’s a Tunisian professional tennis player who is ranked among the top ten women players on tour. I find her story of building an all-Tunisian team and representing the African continent incredibly inspiring. I would love the opportunity to discuss her journey, delve into her mental strength, and perhaps ask if I could be her player box guest at Wimbledon!

If you were being introduced on stage, what song would you want played that best represents you, and why that song? “Scars to Your Beautiful” by Alessia Cara. I think the song is positive and empowering!

England, Wales and Scotland all now in favour of Irish unification, research shows

The 2023 state of the union survey examines attitudes towards constitutional issues in the uk.

New research reveals the differing attitudes to potential Irish unification held among the English, the Scots and the Welsh. Photograph: iStock

Opinion in England, Scotland and Wales now favours Irish unity, according to major new research.

In the past, research has tested the waters about opinions in Great Britain taken as a whole towards Irish unification. Now, however, new research sheds light on the differing attitudes held about such an outcome among the English, the Scots and the Welsh separately.

The information is included in an analysis of the 2023 State of the Union survey probing attitudes towards constitutional issues in the UK carried out by leading academics, Ailsa Henderson and Richard Wyn Jones.

Instead of getting a simple Yes, No answer from those polled, people were asked to place their attitudes about unification and other issues on a sliding scale from minus 10, or Definitely Not, to plus 10, Definitely Yes.

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Asked if Northern Ireland should unite with the Republic, Scots placed themselves at 1.9 on the positive side of the scale, England came in at 0.9, Wales at 0.6, even with those polled in Northern Ireland at 0.6 on the positive scale in favour.

However, the detailed breakdown illustrates sharp divisions in NI society, with 31 per cent saying Irish unity is something they “definitely do not want”, while a slightly smaller number, 28 per cent, say they “definitely do want it”.

“Attitudes about reunification are strikingly different. Attitudes in Northern Ireland itself fall very near the midpoint. But the electorates in England, Scotland and Wales are each more supportive of reunification,” say the two academics.

The findings, though more complicated than simple Yes, No questions, are significant, says professor of political science at the University of Edinburgh, Ailsa Henderson, who will present findings on Thursday in Belfast at the Imagine! festival.

“The balance in England and Wales is negative towards independence for Scotland and about independence for their own territories. What is noteworthy about attitudes to NI, however, is that everyone in England, Scotland and Wales is above the midpoint about its future,” she says, emphasising the word “everyone”.

And there is drift in the numbers compared with the 2021 State of the Union Survey: “We have seen opinion in Northern Ireland [about unification] move to the other side of the midpoint. Barely, but it is now above the midpoint,” she says.

Scotland is most enthusiastic about independence for Northern Ireland, along the lines of “Go forth and prosper, friend”, but support for Irish unity in Wales and England could be interpreted more negatively, rather like wishing for the departure of a problem.

Graphic: Paul Scott

The Scottish view, says Henderson, is “a genuine wish” for Irish unity and for Northern Ireland to have the constitutional future that it wants to have: “So, if we can’t break free, then maybe you can, that sort of thing.

“There are different reasons in different parts of the UK explaining the views taken about Northern Ireland leaving the Union. In England, it’s probably more the ‘bugger off’ variety. In Scotland, it’s probably, ‘Go and live your best life’.

“The idea that a majority in three nations in a multi-state union with varying levels of intensity favour the departure of the fourth nation in that union is highly unusual,” says Richard Wyn Jones, professor of Welsh politics and director of Cardiff University’s Wales Governance Centre.

“This is very significant. Attitudes towards Northern Ireland look very, very different from attitudes elsewhere. It is highly unusual in a multinational state, or whatever you describe the UK as, that the aggregate in Scotland and England and Wales is that Ireland should be unified,” he says.

However, he cautions: “What is different about what we are doing is to take the UK seriously as a four-nation state.

“It is very difficult to get comparative data. People usually talk about ‘attitudes in Britain’ without disaggregating England and Wales.

“We take the UK seriously as a four-nation state. We need to be slightly cautious about whether attitudes are developing. We can’t tell you what was going on five years ago, or 10 years ago.

“One would need to be quite careful about jumping to any big conclusions,” he says. However, attitudes about Brexit shown in the 2021 survey offers some guidance, Henderson says, since 62 per cent of Leave voters in England, 69 per cent of those who voted for Brexit in Wales then regarded the Irish Sea “border” as a price worth paying for Brexit.

“It is also the case that more than half of voters in England and Wales say they either wanted an Irish Sea border anyway, or that it is a price worth paying for Brexit,” the 2021 survey carried out by the same two academics records.

“There is this sense that Northern Ireland is seen as a more expendable part of the United Kingdom than other parts. But it’s also the case that every time we ask about Northern Ireland, the “don’t know’ figures just jump through the roof,” says Henderson.

The political controversy in London over recent years about the post-Brexit landscape perfectly mirrors attitudes held by a majority in England and Wales and, to a lesser extent, Scotland about the future of NI, says Wyn Jones.

“The bottom line is the fact that Northern Ireland, from a unionist perspective, has been sacrificed for Brexit is entirely consistent with public attitudes in the rest of the UK,” said Wyn Jones.

“The views about Northern Ireland and the territorial integrity of the UK in relation to it are different from attitudes towards the territorial integrity of Great Britain. There’s an obvious difference there,” he says.

Questions about the share of Treasury funding going to each of the UK nations reveal significant disagreements about the sums allocated under the long-standing, but complicated Barnett Formula .

“We’re able to demonstrate quite consistently that everyone thinks their own part is getting less, and everyone outside England thinks that England is the one that’s getting more,” says Henderson.

However, attitudes in England towards the money that Northern Ireland gets from the Treasury – even though NI argues that it is not getting a fair share – “are much more benign than they are about Scotland’s share of resources”.

“The Scottish question is always the one that causes the greatest negativity in England. Northern Ireland doesn’t seem to tap into the English sense of grievance in the same way that Scotland does,” she says.

So what does all this say about the durability of the United Kingdom? For Wyn Jones, it shows that attitudes are focused close to home: “What politicians often project as commitment to the UK and the Union just isn’t there in public attitudes,” he says.

Agreeing, Henderson says the attachment to the UK’s territorial integrity stops “at the borders of Great Britain and does not extend to NI in the same way it does if people there contemplate the departure of Scotland or England or Wales”.

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Mark Hennessy is Ireland and Britain Editor with The Irish Times

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Florida news | rep. carolina amesty notarized document that teacher says he never signed | special report, florida news, subscriber only, florida news | go inside research boat that studies florida’s overheated corals.

While you might first notice the glossy super yachts or a fishing trawler on the Miami River, there’s also an 80-foot vessel packed not with partiers, but scientists, trying to protect the coral offshore.

Bridget Coughlin, the CEO of the Chicago-based Shedd Aquarium, said their research vessel named the Coral Reef II is docked in Miami because of the diversity of marine life in the area.

“We teach climate change through empathy with animals,” said Coughlin. “If you talk about how otters are starving, that empathy for that otter is going to catalyze you to act.”

The vessel can go out to sea for three weeks at a time and can travel as far south as the Dominican Republic. The researchers study a plethora of animals including queen conch, endangered rock iguanas, sharks and climate change’s impact on the coral reef. From March through October, the crew often works days that stretch from 7 a.m. to midnight.

How to come aboard the research vessel

The Coral Reef II also acts as a live-in laboratory for aspiring marine biologists. High school and college students can go on a weeks-long journey that includes snorkeling in crystal-clear water with Caribbean reef sharks and working side-by-side with scientists. Chuck Knapp, a 30-year employee of Shedd and the head of conservation on the vessel, said he got his start that way.

Rep. Carolina Amesty notarized document that teacher says he never signed

“I was originally a high school marine biology student back on the boat as a 17-year-old in the late ‘80s so it’s been a thrill of a lifetime to come back,” Knapp, who gave a tour of the vessel in the video said.

This summer, high schoolers will be taking a trip to the Bahamas to learn about how to protect dolphins, snorkel shipwrecks and observe firsthand from Shedd’s shark research biologist.

Conducting research on coral reefs bleaching

One of the most unique parts of the vessel is its live well system, which consists of large built-in tanks at the front of the boat filled with seawater.

These mini aquariums are a safe harbor for wildlife that scientists are trying to study or move. The live well system makes it easy to scoop marine life like coral up, perform heat stress tests and return them back to sea in hours.

Ross Cunning, a coral biologist with Shedd, said researchers can use technology onboard to test how well the coral absorbs sunlight and observe what temperature and speed cause corals to bleach.

Even two corals of the same species might bleach at different speeds, and they’re looking for the most heat tolerant coral, Cunning said.

Last summer he worked alongside South Florida research groups, like the University of Miami, the Coral Restoration Foundation, and Reef Renewal to test snippets of these baby corals in nurseries that have been growing in higher water temperatures.

“Finding interventions to boost the heat tolerance in coral reefs is more important than ever,” Cunning said. “But the most critical thing we need to do is stop climate change.

“All the research in the world will not boost coral heat tolerance enough to cope with oceans that continue warming. We must stop the root of the problem and stop greenhouse gas emissions as quickly as possible.”

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Despite bans in some states, more than a million abortions were provided in 2023

Selena Simmons-Duffin

More than a million abortions were provided in the U.S. in 2023. That's a major finding from a report published Tuesday by the Guttmacher Institute, a research organization that supports access to abortion.

To be precise, researchers estimate there were 1,026,700 abortions in 2023. "That's the highest number in over a decade, [and] the first time there have been over a million abortions provided in the U.S. formal health care system since 2012," explains Isaac Maddow-Zimet , a data scientist with Guttmacher.

The Guttmacher report also found that medication abortions rose to 63% of all abortions in 2023, up from 53% in 2020. The research was conducted by surveying all in-person and virtual abortion providers in the country and adding up their abortion counts. Guttmacher has been doing this research since 1974.

The findings do not surprise Dr. Anitra Beasley , an OB-GYN and professor at Baylor College of Medicine in Houston, who was not involved in the study. She says the trend was suggested by earlier research – and in fact she thinks the true number is even higher than what was measured in the report.

"This is probably an undercount because they are not looking at abortions that happen outside of the formal health care system," she explains. Uncounted abortions include those that happen when someone gets abortion medication from a friend or over-the-counter at a pharmacy in Mexico, for example.

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Abortion pills that patients got via telehealth and the mail are safe, study finds.

She says those "self-managed" abortions are certainly happening, but it's extremely hard to measure them in national counts.

The fact that the number of abortions continues to rise may be counterintuitive given the fact that the U.S. Supreme Court overturned Roe v. Wade in 2022. Access to abortion has been severely restricted in more than a dozen states since the last time Guttmacher published a comprehensive national count. In 2020, Guttmacher reported that there were 930,160 abortions in the U.S.

The share of abortions that are performed with medication alone (a combination of mifepristone and misoprosotol) increased between 2020 and 2023. Rachel Woolf/The Washington Post via Getty Images hide caption

The share of abortions that are performed with medication alone (a combination of mifepristone and misoprosotol) increased between 2020 and 2023.

"Certainly the increase in availability of medication abortion through telemedicine is a big part of this story – that's something that really wasn't largely available in much of 2020 and is much more available now," Maddow-Zimet says. "But we also saw increases in the proportion of abortions provided through medication abortion at brick-and-mortar facilities as well."

Under current FDA prescribing rules, medication can be used to end a pregnancy until 10 weeks of pregnancy, and it can be prescribed through a virtual appointment without affecting the medication's safety or efficacy.

Those rules are the focus of another Supreme Court case scheduled to be argued next week. A group of anti-abortion rights plaintiffs will argue that FDA incorrectly decided to simplify access to mifepristone, one of two medicines used in medication abortions. The high court's decision, expected this summer, could upend access to mifepristone for abortion and miscarriage care.

"We don't know what the Supreme Court will decide, and we don't know exactly what the impact will be, except that it will create potentially more of that confusion and difficulty for people both providing care and needing to access care," Maddow-Zimet says.

He adds that although tens of thousands of people living in states where abortion is banned have been able to travel to receive abortions, and clinics and abortion funds have scaled up to meet the demand of traveling patients, it's unclear if that can continue long term.

Beasley agrees. "It's really important to realize that the increase in abortion access [despite restrictions] is not an accident," she says. "It's a lot of people working really, really, really hard in order to make sure that abortion is still accessible to people who need it. So even though the top line number is higher, it does not mean that access is overall better."

When it comes to the landscape of reproductive health access after the fall of Roe v. Wade , Maddow-Zimet says, "we don't know what normal looks like in this context – policies keep changing, we keep seeing really big changes in access."

• medication abortion

Medical Writing pp 219–237 Cite as

9 How to Write a Research Protocol

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No football coach would ever let his team take the field without a “game plan.” The research protocol is the game plan for your project, your vision of what you will accomplish when you “take the field” with your research team. The document describes the reasoning behind and the process of the research project that you have in mind [1]. It tells what you hope to accomplish and how you will get it done. It also imposes a discipline, requiring you and your team to anticipate every step of the project before the first subject is recruited. This body of the research protocol more-or-less follows the IMRAD model, an acronym for the words Introduction, Methods, Results, and Discussion. We will return to this model in Chap. 11, which discusses how to write a report of a research study.

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Taylor, R.B. (2012). 9 How to Write a Research Protocol. In: Medical Writing. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8234-6_9

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