Please answer the following bullet pointed questions with at least 1 paragrapgh (7 sentence minimum per paragraph) APA 7^th Edition

A well-designed study will clearly identify an exposure/risk and an outcome in an objective, quantifiable manner to answer a defined hypothesis/research question.

• What barriers or challenges have you encountered?
• How did you handle them?
• Did you need to change/revise your project design?

Topic: A review on how to improve enrollment for 1st time clinical trial pediatric subjects diagnosed with Duchenne Muscular Dystrophy

Draft:

Duchenne Muscular Dystrophy (DMD) is a progressive disorder caused by mutations in the DMD gene. The condition usually starts in childhood and progresses over the lifespan of the individual, significantly reducing the anticipated life expectancy of the person compared to unaffected people’s life expectancy. The disease is caused by genetic mutations in the gene encoding dystrophin which inhibit the production of dystrophin in muscles. Muscles that lack dystrophin are more sensitive to damage and lead to progressive loss of muscle tissue and strength which may lead to cardiomyopathy (Sun et al., 2020). Current management of DMD includes multidisciplinary care to manage the symptoms and promote the quality of life for patients. However, so far, there is no cure for DMD and much of the research has focused on mitigating the progression of the disease and hence prolonging the life of affected people.

Background

Muscle weakness is the main symptom of DMD and it is progressive, starting in childhood. Diagnosis can be made as early as 2 or 3 years of life and muscle weakness first affects the proximal body muscles (Paquin et al., 2019). Later, distal limb muscles are affected, making it challenging to walk. The affected child faces challenges in walking, jumping, and running. Other early symptoms include a waddling gait and posture and lumbar lordosis. As the disease progresses, scoliosis and impaired pulmonary function are expected. These can eventually result in acute respiratory failure and mortality (Paquin et al., 2019). Due to the progressive nature of the condition, current research is focused on finding means of stopping the progression.

Patients with DMD require multidisciplinary care. With optimal care, the lifespan of the patient can be extended into their forties, mainly due to the development of standards of care and guidelines to manage cardiopulmonary function. The life expectancy of patients with DMD has significantly improved over the years. In one study, it was found that patients born before 1970 had a life expectancy of 25.77 years but this has improved to 40.95 years afterwards (Kieny et al., 2013). There are several drugs currently used to promote quality of life with adjunct therapies mainly focusing on patient functionality, disability, and quality of life. Regardless of the progress, DMD patients still lead a poor quality of life and substantially shorter life expectancy compared to the rest of the population. More research and therapy development to inhibit disease progression is thus required.

The development of DMD drug therapies depends on clinical trials especially of pediatric patients to test drug options. The anticipated benefits from clinical trials is not to cure the disease and restore muscle function but rather to inhibit progression of the disease. The recruitment of appropriate candidates for trials, therefore, remains problematic for this and many other reasons. DMD is also a rare disease affecting a relatively small population. As is the case with many other rare chronic conditions, the recruitment of patients to participate in clinical trials remains challenging because of the safety and efficacy concerns as well as ability to access research participants. Disappointment with previous trials that failed to produce results is also a reason for hesitancy of parents to children with DMD (Ryder et al., 2017). It is also unethical and challenging to maintain control groups for such research projects. The recruitment of pediatric patients for DMD research, therefore, remains a challenge for many researchers and it is necessary to determine reliable, effective, and feasible means of recruitment.

Goals and Objectives

The overarching goal of this research is to determine the means that the recruitment of first-time clinical trial pediatric subjects diagnosed with DMD can be improved. The anticipated result is that the research will inform on the most effective means of maximizing recruitment for this target population. To achieve this goal, the following objectives will be pursued:

1. To determine the main barriers to recruiting first-time pediatric participants for DMD clinical trials.
2. To identify methods that researchers have used and deem most effective in recruiting first-time pediatric participants for DMD clinical trials.

Literature Review

Epidemiology

DMD is a genetic x-linked neuromuscular disorder primarily characterized by progressive muscular wasting. The epidemiology of the condition is quite low with the prevalence of 1 out of 5000 males (Paquin et al., 2019). The condition is often diagnosed between 2 and 5 years and can be noted as weakened proximal muscles, delay in motor development, and abnormal gait (Guiraud & Davies, 2017). It is the most common of muscular dystrophy conditions and typically affects males (Paquin et al., 2019). The condition affects approximately 250,000 people in the United States with thousands of others in other countries and regions or with unreported diagnoses (Ryder et al., 2017). The quality of life for people with DMD is significantly affected by muscular dystrophy hence the need for ongoing research on its treatment and slowing the condition’s progress.

Although DMD is typically expressed in males, females can be carriers of the recessive gene. Most females who are carriers of the gene will not develop DMD. Some, however, may develop a similar condition, Becker Muscular Dystrophy (BMD), which is milder and has typical onset during teenage (Ishizaki et al., 2018). Female carriers may be asymptomatic but up to 19% may develop skeletal muscle problems with dilated cardiomyopathy (Ishizaki et al., 2018). However, they do not develop respiratory symptoms. One study in Scotland showed that carriers of DMD and BMD genes have a similar lifespan as unaffected people (Holloway et al., 2008). Therefore, DMD typically affects males and in the case of symptomatic females, the symptoms are mild with little or no change in their impairment and lifespan.

The rate of progression for DMD may vary from one patient to another. Typically, the patient is diagnosed with delayed motor development and abnormal gait with muscular dystrophy (Guiraud & Davies, 2017). This will then progress to loss of independent motor function with the patient eventually requiring assistive technology for ambulation (Paquin et al., 2019). Loss of arm function is also experienced at the same time. Eventually, the patient will succumb to cardiovascular and pulmonary failure (Guiraud & Davies, 2017). The average lifespan is between 20 and 30 years and hence the patients experience premature death (Guiraud & Davies, 2017). During the relatively short lifespan, loss of independent function and progressive muscle dystrophy have significant challenges on the patient and their caregivers.

Treatments

Non-curative treatments have been developed and implemented in the US with little success. Treatments can be classified as therapies targeting the DMD defect and those mitigating secondary pathologies and mechanisms. Currently, only two treatments specifically targeting DMD defect have been approved in the US. The first is corticosteroid therapy used to slow the progress of symptoms and muscular degeneration (Paquin et al., 2019). The second therapy is genetic therapy specifically targeting mutations in the DMD gene (Paquin et al., 2019). While corticosteroids are indicated for all patients, genetic therapy is limited to only about 15% of the population with DMD but the efficacy is not yet ascertained (Paquin et al., 2019). Thus, urgent research on drugs and therapies for DMD is needed to address the current gap in treatment.

Gene editing presents hope in the treatment of the causes of DMD. In BMD, dystrophin proteins are smaller and partially functional, leading to mild illness. In DMD, gene point mutations, duplications, and deletions are noted, interrupting the genetic reading frame (Duan et al., 2021). Gene editing technology, CRISPR, has successfully been used to improve heart function in animals with DMD by 80% in only eight weeks (Amoasii et al., 2018). The technology has also been successfully used to edit DMD genes in cells from people with DMD (Dara et al., 2021). Large clinical trials to test the efficacy of the therapy and its safety are needed before it can be authorized and widely used to treat patients with DMD. Recruiting pediatric patients with DMD for these clinical trials is needed to assist in developing the proposed therapy.

Challenges in Previous Studies

Previous researchers have encountered numerous enrollment challenges, especially because DMD is a rare disease and there is also consideration for treatment-amenable genetic subtypes (Peay et al., 2016). With only 250,000 people in the US as captured by Ryder et al. (2017), it is challenging to access a sample population that can amount to a credible and reliable research outcome. Even in cases where patients are obtained, spatial challenges in conducting research are common (Duan et al., 2021). Additionally, genetic subtypes also differ in DMD and enrolling patients for a specific subtype has proved further challenging (Peay et al., 2016). Therefore, the primary challenge experienced is the rarity of the disease and accessing appropriate population.

Another challenge is the practical and ethical challenge of conducting placebo arms for this condition.DMD is a progressive condition leading to ultimate death and the aim of almost all the studies is to slow down progression or stop the progression overall (Goemans et al., 2020). Therefore, to determine drug effectiveness in real-world data and natural history data, it is required that a control group is maintained to ensure that changes in the intervention group can be properly attributed to the treatment (Goemans et al., 2020). It is unethical to withhold potentially life-saving medications from patients who face imminent death from a health condition (Goemans et al., 2020). Therefore, recruiting and maintaining patients for both the intervention and placebo groups remains a major challenge.

The concept of informed consent and deliberations for ongoing controlled trials is another issue. DMD trials are typically conducted with pediatrics and this means informed consent can only be granted by a parent or guardian (Peay et al., 2016). Therefore, when recruiting subjects for participation in clinical trials, the concept of consent must be considered at the point of view of the parent. Informed consent is an ongoing process of deliberation where the decision-makers access information, appraise it, and make decisions based on it (Peay et al., 2016). New and emerging information may dissuade parents from the trials and disagreements between pediatrics and their parents on participation may also hinder the process (Peay et al., 2016). Despite efforts to use patient-focused drug development (PFDD), informed consent and subjective patient experiences are not adequately captured in such trials (Crossnohere et al., 2020).

Perceived Benefits and Harms

Parents and their children considering entering a DMD or another clinical trial will consider benefits and costs of participating and this will significantly affect their willingness to participate. Benefits of participating can be defined as any additional gain the patient or family have from the study and range from better health outcomes to access to therapy options (Peay et al., 2016). Harms include any psychological or physiological harm caused including worsened health condition or disappointment from the trial (Peay et al., 2016). As such, the patient and their family’s understanding of the history of disease, research, and participation in prior studies may affect their willingness to participate in DMD trials (Naarding et al., 2020).

Parents to children with life-limiting disorders mostly make decisions to participate in clinical trials with the hope for individual benefit of the child and the perceived benefit of treatment at no extra costs (Peay et al., 2016). The possibility of health improvement from participating in clinical trials is a motivating factor for most parents. Parents with children with life-limiting disorders such as DMD find it challenging to decline participation compared to those of children in stable health (Naarding et al., 2020). Most parents also expect that if the trial is a success, their children are receiving treatment at no extra costs. This presents a challenge as Crossnohere et al. (2020) noted that many parents do not differentiate treatment options and clinical trials participation options. While clinical trials may offer free drugs or treatment under certain conditions, this is not always the promise in all trials.

Additionally, hopefulness and access to the latest treatment options is another motivator established by Crossnohere et al. (2020). The psychology of parents and others participating in clinical trials is that they maintain hope in obtaining a treatment that is helpful in various ways. Hope, therefore, is a concept central to the recruitment process. It is closely linked to access to the latest treatment options by the assumption that newer treatments will be more effective or safer than older treatments (Crossnohere et al., 2020). One downside of hopefulness is that patients and their families may experience negative psychological outcomes in cases when trials are not successful (Peay et al., 2016). As a result, failed clinical trials may lead to increase in desperation, anxiety, and depressive symptoms for patients and their parents.

Some of the harms considered include randomization, time, and inconveniences caused by the studies (Crossnohere et al., 2020). Randomization is the process of allocating patients randomly to the intervention and placebo arms of a clinical trials and in blinded studies, the patients and their parents are not aware which group they belong in (Crossnohere et al., 2020). Time taken in clinical trials that may span years may also come with inconveniences such as the need to travel and collect data (Crossnohere et al., 2020). These perceived harms may discourage patients and their parents from participating. A sense of helplessness and hopelessness may also be present in some patients who have participated in previous studies to no success (Crossnohere et al., 2020). Generally, current literature shows that most parents will consider the cost-benefit analysis as an effective means of determining whether to participate.

DMD clinical trials are currently challenged in recruiting pediatric research subjects for many reasons. The condition is progressive, leading to loss of functional independence and ultimate death. Current treatments using corticosteroids aim to reduce the progression while genetic therapy is still ongoing to target the gene mutations for the disease. Current literature shows that researchers face significant challenges when recruiting participants and participants and their parents conduct a risk-benefit analysis of the clinical trials to determine whether to participate. Further research on means of motivating participants while minimizing potential harms is needed to support DMD research.

Methods

Research Design

The design of the proposed research is a descriptive survey combining both quantitative and qualitative approaches. The research will use survey questionnaires to collect data and opinions from research participants on the recruitment approaches for DMD clinical trials. Therefore, the information sought from the study is generally descriptive of the participants’ experiences and preferences when recruiting for first-time clinical trials. The descriptive survey will be conducted through questionnaires issued to research participants.

Setting and Participants

Owing to the rarity of DMD in the general population, the setting of this research will be generalized to the entire United States. Participants will be accessed via the Duchenne Registry https://www.duchenneregistry.org/, a self-report registry in which parents of children with DMD and adults with DMD enter data about their progress and access research and clinical trials. The registry extends beyond the United States but when searching for research participants, recruitment will be narrowed to the US. The setting is, therefore, the general population with the common characteristic being registered on the Duchenne registry. The registry is an advocacy for patients with DMD and thus represents patients who are more likely to be recruited for DMD clinical trials (Peay et al., 2016). It is appropriate for this descriptive research.

The participants for this study will be parents to children with DMD. Since the condition has an early onset in childhood, parents and legal guardians have the authority to consent and participate in research. Therefore, targeting these parents and legal guardians is ethically permissible and useful in learning about DMD clinical trials recruitment. In general, participants will be parents or legal guardians of pediatric patients with DMD who are accessible via the registry or clinical referrals.

The study will include a random sample of parents or legal guardians to children with DMD. Participants will be considered if they are a parent or legal guardian to child with DMD, the child represented has a medical diagnosis and is below 18 years, and has had the diagnosis for at least 6 months. Also, participants should not have participated in any clinical trials in the past (1^st-time recruitment) and should be resident in the United States.

Potential research participants will be excluded is the parent or legal guardian does not live with the DMD patient, they have previously participated in a clinical trial specific to DMD, or the parent or legal guardian cannot understand and respond to written English. Patients with DMD symptoms but no medical diagnosis has been made will also be excluded.

Sampling and Recruitment

Simple random sampling will be used for the study design. After the sample frame has been narrowed using the inclusion and exclusion criteria, a random sample of 20 participants will be selected using Research Randomizer (Social Psychology Network), an online randomizing program. The researcher will directly contact potential participants using email or newsletter for recruitment. A consent form will be sent alongside the email or newsletter which, if potential participants agree to participating, should fill and return via email. Potential participants who decline to participate or fail to respond will be replaced by others randomized from the remaining pool of unselected potential participants.

Data Collection and Analysis Procedures

After participants consent to the research, a questionnaire will be sent via email or preferred communication platform. The questionnaire (Appendix A), will be filled and returned to the researchers via email. The researcher will make direct calls to the participants to discuss the questionnaire, expectations, and clarify any unclear information regarding research purpose, consent, and responses. Once returned to the researcher, the questionnaires will be analyzed thematically and statistically. Thematic analysis will include coding of the major themes expressed in response to questionnaire questions until saturation of themes is achieved. Statistical analyses will be conducted using Microsoft Excel to outline descriptive statistical outcomes of the demographics as well as research participants’ preferences and opinions.

Ethical Considerations

The main ethical considerations for the research include informed consent, research approval, and participant confidentiality. Informed consent will be obtained by sending potential participants a consent form outlining the purpose of the study, expected data use, and all pertinent information regarding the research. Researchers will call participants and discuss the consent form and general research aspects with them to ensure clarity. Research approval will be obtained from the institutional review board based on the protocol provided here. Confidentiality of the participants will be ensured by de-identifying data obtained through questionnaires. No personally-identifiable data will be collected and participants will be instructed not to indicate their name or any other personally identifiable information on the questionnaire. The researcher will maintain confidentiality of the participants’ identity and no personal information will be shared in the research report. No safety concerns are foreseen in this study. Participants will be free to discontinue the study with no consequences or withdraw their data from the research.

Avoiding Bias

The study presents potential bias in recruiting participants from an advocacy group. The recruitment reduces heterogeneity of the research participants and presents potential bias. Despite this limitation, DMD patients and parents/legal guardians on the registry are more likely than others to participate in clinical trials. This is because they already show interest by registering on a platform that promotes research and clinical trials. The registry also presents convenience in accessing participants who may be challenging to identify in the general population due to the rarity of the disease. To minimize biases and determine validity of the research, future studies should focus on a more heterogeneous participant group where recruitment is conducted in the community in the general population of patients with DMD.

Results

There are several anticipated results from this research effort. A preliminary feasibility study with fellow students in clinical trials studies was conducted to provide an overview of anticipated recruitment techniques from the proposed study. The participants were students in a clinical research program in a single institution. Several findings were obtained from this research.

Current Recruitment Practices

There are numerous recruitment channels for DMD patients to be included in clinical trials. However, students and researchers in the field have identified that the most used channel is site database search followed by written publication advertisements and then recruitment companies. Site database searches are especially useful when the target population is not easy to access in the general public population. Written or published advertisements target the general population and are more reliable due to the heterogeneity of research participants achieved (Clark et al., 2019). However, with DMD, accessing an adequate number participants may be challenging. When using recruitment companies, the researchers reduce their workload by delegating recruitment. While this process may make it easier, the reliability of the recruitment process is only as good as the company assigned that role.

Main Concerns and Issues with Recruitment

Failure to participate in clinical trials for DMD may be due to various reasons. In the preliminary research, several concerns and issues were identified. The most common concern is the lack of education on the clinical trial process. Many potential participants lack information and knowledge on the clinical trial process and hence may be unwilling or unable to participate. Additionally, travel concerns are also a major issue. This is especially important for patients with DMD. Limitations in mobility and ambulation challenges often require special traveling and accommodation arrangements to meet the patients’ needs. Assisted ventilation is a major concern for many patients who may be unable to travel long distances (Janisch et al., 2020). Complex travel arrangements may be needed for research participants. The other common concern is scheduling. Working with the schedules of patients and their primary caregivers can be challenging and together with travel concerns, these are logistics challenges that may be especially pronounced for DMD patients. Other concerns identified include lack of trust with researchers and personal information as well as lack of reimbursement.

Recommendations on Recruitment Techniques

Moreover, when asked about their views on recruitment techniques, the participants in the preliminary study identified additional resources such as social workers, marketing techniques to reach a wider audience, remote collaboration platforms, and collaboration with advocacy groups to identify the most relevant potential participants. Additional resources such as social workers can be deployed to reach out to the patients, discuss the study, and concerns about participation. Marketing techniques can enhance education to patients and their caregivers and prompt interest. Remote collaboration platforms can enhance follow-up and ensure better connection of patients with the researchers. Advocacy groups such as the Duchenne Registry present access to potential participants and hence can promote participation.

Discussion

Numerous barriers exist limiting first-time participation in DMD clinical trials and better recruitment methods can help address those barriers. Many clinical trials in the past have experienced low participation rates or long recruitment periods. Barriers such as patients’ travel concerns, scheduling problems, and lack of knowledge have limited participation in clinical trials, making the process challenging for researchers. The reliability and validity of research with limited participation are also significantly challenged. The proposed study will evaluate parents and legal guardians to pediatric patients with DMD to determine techniques that can promote their recruitment for clinical trials. Findings will help researchers to implement better clinical trial recruitment techniques to promote the efficacy of clinical trials and the validity and reliability of findings on drug efficacy and safety.

Recruitment for DMD clinical trials is most effective if a multi-stakeholder approach is employed. Major stakeholders include patients, caregivers, physicians and healthcare organizations, and advocacy groups. Accessing the potential participants’ needs consideration of all these stakeholders and consulting on the best means to access and retain patients. For instance, understanding where DMD patients mostly seek health care can provide an opportunity to directly target them through the healthcare facility (Huang et al., 2018). Working with the caregiver and the patient can alleviate problems of travel and scheduling concerns. Working with an advocacy group is good in accessing potential participants but it is not adequate to maximize the recruitment process; hence, there is need for multi-stakeholder consideration and collaboration.

Additionally, establishing a centralized database or registry accessible to researchers and DMD patients is crucial. Many patients may lack knowledge about existing clinical trials and the clinical trial process. Misinformation such as the belief that being involved in the trial automatically leads to health improvement may be misleading. Similarly, a study in the UK found that 91% of patients are willing to participate in clinical trials but majority feel a sense of desperation about accessing clinical trials (Straub et al., 2018). Following the findings, Duchenne UK created the DMD Hub, a national database where patients and researchers can interact and ease the recruitment process. The Duchenne Registry is a similar platform but many patients may be unaware of it. Popularizing such platforms through marketing can enhance knowledge and access to clinical trials for patients while increasing the ease of recruiting DMD patients.

Another theme that comes out clearly in current research is the importance of ongoing communication during and after recruitment. During recruitment, the ability to communicate remotely using technologies such as teleconferencing may maintain interest in the clinical trial (Huang et al., 2018). After recruitment, remote communication can help enhance completion rates. Innovation in ongoing communication with patients is necessary to ensure access and maintain their interest in the clinical trial. It also reduces scheduling and travel concerns, essentially making it easier for participants to adhere to the treatment offered and reducing drop-out rates.

Lastly, collaborating with social workers is also a feasible and potentially helpful method of enhancing DMD clinical trials recruitment. The overall role of the social worker is to promote the welfare of their clients. In clinical trials, social workers play the role of a counselor, patient advocate, and conduit in the research process (Peterson et al., 2018). When involved in recruiting for DMD clinical trials, social workers can help potential participants understand the protocol, potential harms, and potential benefits. They can add clarity to the clinical trial and hence boost trust. Parents and guardians to DMD children can directly consult social workers when they have concerns and as a mediator between the researcher and research participant, the social worker may be more relatable to the participants than the researcher.

Conclusion

Researchers running clinical trials for DMD therapies have long faced barriers and challenges recruiting participants to their trials. It is thus necessary to determine more feasible, reliable, and valid approaches to boosting recruitment. Targeting parents and legal guardians to pediatrics with DMD, the proposed study will evaluate the most appropriate means of recruitment and retention. A descriptive survey will be conducted with participants accessed via the Duchenne Registry to determine their views and experiences on recruitment. Preliminary research shows that a multi-stakeholder collaboration, central registries, innovative communication, and social workers may be useful in promoting recruitment. Findings from the study will assist in accelerating DMD therapy research and advancing solutions that can improve patients’ quality of life, lifespan, and health outcomes.

References

Amoasii, L., Hildyard, J. C., Li, H., Sanchez-Ortiz, E., Mireault, A., Caballero, D., & Olson, E. N. (2018). Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science, 362(6410), 86-91. https://doi.org/10.1126/science.aau1549

Clark, L. T., Watkins, L., Piña, I. L., Elmer, M., Akinboboye, O., Gorham, M., & Regnante, J. M. (2019). Increasing diversity in clinical trials: Overcoming crit