Strategies to Enhance Pediatric Clinical Trial Participation : Indian Journal of Paediatric Dermatology

Secondary Logo

Journal Logo

Hot Topics in Pediatric Dermatology

Strategies to Enhance Pediatric Clinical Trial Participation

Manobalan, K.; Gupta, Divya1,2,

Author Information
Indian Journal of Paediatric Dermatology: Oct–Dec 2022 - Volume 23 - Issue 4 - p 268-270
doi: 10.4103/ijpd.ijpd_79_22
  • Open

Recruitment has been identified as a key barrier in conducting pediatric trials. However, there is not much information on evidence-based strategies to improve the recruitment of children for pediatric clinical trials. In this systematic review, the authors identified strategies to enhance pediatric clinical trial participation. Searches were conducted in MEDLINE/PubMed, EMBASE, and Web of Science. Eighty studies were included although none were pediatric dermatology specific.[1] Interestingly, out of 80 studies, only one was a randomized controlled trial. The various strategies were categorized by the authors as follows:

  • Protocol development/pretrial planning (36 studies; 45%): One of the most common approaches used was for the trial protocol to be convenient for patients and families. Specifically, it entailed being flexible about when, where, and how data were collected, minimizing time commitment, providing services such as transportation or childcare, and budgeting for these things accordingly.
  • Trial marketing (27 studies; 33.8%): Many studies suggested utilizing traditional advertising methods, such as advertisements in newspapers, televisions, radios, posters, or letters sent directly to families by mail, along with “opt-out” messaging, where families are automatically called with more trial information unless requested otherwise
  • Educational tools (22 studies; 27.5%): Common recommendations included creating study-specific websites or social media pages on Facebook that comprehensively displayed study information. One paper recommended replacing the traditional trial information sheets with colorful pictures and visual aids to help children understand trial information. Other studies recommended short educational videos to describe the trial, the benefits of participation, and the experiences of previous participants
  • Communication strategies (53 studies; 66.3%) at the time of recruitment: these include emphasizing trial benefits to the patients, educating them about how they will be contributing to the scientific literature about the disease, and focusing on addressing parental concerns. For older children and adolescents, talking to them directly and explaining the study in a simple language make them feel more involved in the decision-making process
  • Community involvement (17 studies; 21.3%): These studies recommended that recruiters consider taking the school personnel/staff (e.g., school superintendents, teachers, principals, and nurses) into confidence to enhance community participation in clinical trials. This would be more representative of the community, as opposed to clinic-based participation, which can suffer from selection bias. School assemblies and occasions where parents are present at school (such as registration days, school fests, and open house) were other suggested methods to engage children as well as parents
  • Incentives (13 studies; 16.3%): These studies suggested financial reimbursement for travel, loss of wages, and time spent at the hospital. Nonfinancial incentives such as food and play area for children were also suggested.

The review is pertinent for the current times because conducting clinical trials is quite challenging, and more so, if the trial happens to be in vulnerable populations such as pediatric age group.[2] Children are often the last to benefit from any advances in medicine because of inherent risk of participating in clinical trials. In addition, in developing countries like India, where overall levels of literacy including parental literacy are low, children are even more vulnerable. The concept of research is not well understood by many parents/guardians, and it is often mistakenly understood as new or better treatment. The parents may also be unduly susceptible to financial compensation that is offered as part of research, because of their poor socioeconomic status. To protect patients’ interests, the Indian Council of Medical Research came up with National Ethical Guidelines for Biomedical Research involving Children in 2017.[3] Salient points include taking consent as well as assent for children over 5 years of age, providing for compensation, Data and Safety Monitoring Board, and in case of clinical trials, registration with Clinical Trials Registry of India, audio-visual consent, and taking a clinical trial insurance. While these provisions are important to safeguard the interests of the participants, they often make recruitment quite a cumbersome and uphill task, even for investigator-initiated academic trials, where there are no pharmaceutical sponsors. This systematic review provides an overview of strategies that could potentially be useful in enhancing participation in not just pediatric clinical trials but also for observational studies in children. It is not practical or even necessary to incorporate every suggestion. Depending on our cultural context, it may make more sense to apply strategies in the categories of pretrial planning, communication, educational tools, and incentives, whereas other strategies such as trial marketing and community involvement may not be very relevant.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. McKenzie PL, Siegel DH, Cullen D, Castelo-Soccio L. Strategies to enhance pediatric clinical trial participation: A systematic review with narrative synthesis. Pediatr Dermatol 2021;38:1515-22.
  2. Agnihotri G, Lio PA, Lee KC. Differences in pediatric versus adult clinical trial characteristics for atopic dermatitis. Pediatr Dermatol 2021;38:775-9.
  3. Indian Council for Medical Research. National Ethical Guidelines for Biomedical Research Involving Children. Indian Council for Medical Research; 2017. Available from: https://main.icmr.nic.in/guidelines?field_select_disease_tid=97. [Last accessed on 2022 Jul 15].

Cannabinoids: The Silver Lining in Pain Management of Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a heterogenous congenital blistering disorder that manifests with blisters and painful erosions on the skin and mucosa even with trivial trauma. Pain is the most debilitating symptom encountered by the patients with various types of EB. Topical therapies such as lidocaine gel are often ineffective. Since long-term analgesic therapy is usually indicated, there are concerns about morphine and other analgesic treatments (tramadol, gabapentin, pregabalin, amitriptyline, nonsteroidal anti-inflammatory drugs [NSAIDs], etc.) because of opiate/drug dependence and their potential side effects on chronic use. Owing to this, conventional therapies for pain management often do not work in these patients.

In recent times, cannabinoids (tetrahydrocannabinol [THC] and cannabidiol [CBD]) have emerged as an alternative in the pain management of EB, though the literature on this is rather sparse. They interact with the endogenous cannabinoid-binding receptors, activating various cascading pathways.[12] In a recent publication,[2] the authors reported a case wherein they administered oral CBD drops containing 20% phyto-CBD (purity >99.8%, without delta-9-THC) for pain relief in a child with EB as per the manufacturer’s (Trigal Pharma GmbH, Austria, Vienna) standard dosage recommendations. The initial dose of 62 mg (10 drops, 1.6 mg/kg body weight) twice daily was maintained for 6 weeks and then increased to 124 mg (20 drops, 3.1 mg/kg body weight) twice daily. This regimen not only resulted in pain reduction on a visual analog scale but also improved swallowing and patient’s self-reported health status, quality of life, and emotional state. The pain recurred on decreasing the dose of the medication, and the same had to be titrated back to the earlier dose.

There are two things to be considered here. First, it is the THC component of the cannabis that has psychoactive property and consequently can have abuse potential. The authors here used a preparation that contained only CBD, which does not have any psychoactive property, and hence is devoid of abuse potential. In fact, the above preparation is also FDA approved for the treatment of seizures in Dravet syndrome (an early childhood seizure syndrome).[3]

Second, one needs to consider the legal status of prescribing cannabis-based medicines (CBMs - available as topical preparations in oil, sublingual, and systemic formulation). Currently, cannabinoids are legally approved for medical use in the USA, Austria, Australia, Canada, Germany, New Zealand, and Switzerland. The legal status of cannabis products in India remains unclear. There are companies that are marketing cannabis for medical purposes in India under Ayurvedic regulations, and it is likely that there will be more clarity on the issue of CBMs in India in the years to come.[4]

This case report highlights another product in the dermatologists’ armamentarium to bring relief to children with EB. It provides an option that can potentially be used on a long-term basis with fewer side effects compared to opiates or NSAIDs. Although we have anecdotal experience of topical cannabinoid oil for pain relief in a few patients of EB, it is still early days to conclusively comment upon the results.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. Schräder NH, Gorell ES, Stewart RE, Duipmans JC, Harris N, Perez VA, et al. Cannabinoid use and effects in patients with epidermolysis bullosa: An international cross-sectional survey study. Orphanet J Rare Dis 2021;16:377.
  2. Welponer T, Diem A, Nahler G, Laimer M. Purified oral cannabidiol for pain management in severe recessive dystrophic epidermolysis bullosa. Indian J Dermatol Venereol Leprol 2022;88:551-2.
  3. Lattanzi S, Trinka E, Striano P, Rocchi C, Salvemini S, Silvestrini M, et al. Highly purified cannabidiol for epilepsy treatment: A systematic review of epileptic conditions beyond Dravet syndrome and Lennox-Gastaut syndrome. CNS Drugs 2021;35:265-81.
  4. The Narcotic Drug and Psychotropic Substances Act, 1985. Available from: https://legislative.gov.in/sites/default/files/A1985 -61.pdf. [Last accessed on 2022 Jul 15].

A Clinical Scoring System for Pediatric Hand-Foot-Mouth Disease

Hand-foot-mouth disease (HFMD), a viral exanthem that commonly affects children, is caused by Coxsackie virus (CV) A16 and Enterovirus 71. It is clinically characterized by skin lesions of the palms and soles and lesions on the oral mucosa. CV A6, A9, B2, and B5 are the common strains associated with recent outbreaks worldwide and in India.[1]

To ease the clinical diagnosis, Huang et al. have proposed a clinical scoring system for the diagnosis of HFMD.[2] They did a retrospective analysis of the data of 1435 children less than 3 years of age who presented with fever and skin rash and underwent a polymerase chain reaction (PCR) assay. Patients were then divided into the HFMD (1094 patients) group or non-HFMD (341 patients) group based on a positive or a negative result from the assay, respectively. Using a random number selection method, they categorized all the recruits into training set (1004 cases, 70%) and test set (431 cases, 30%). Multivariate logistic regression was performed on 15 clinical variables (related to demographics, rash morphology, distribution across various sites of the body, etc.) to identify variables highly predictive of a positive diagnosis in the training set. Subsequently, the variables with the highest predictive value were used to prepare a scoring system for predicting HFMD, and this was further validated in the test set. Out of the 15 variables tested, seven variables (age of the child; exposure history; number of ulcers on the hard palate, soft palate, and buccal mucosa; and skin lesions on the back and buttocks) were found to be statistically significant and were included in the final scoring model. The severity of the rash was quantified as few (1–3 spots) and many (≥4 spots) for the mucosal lesions, as well as few (1–5 spots) and many (>5 spots) for the skin lesions. Scoring of variables ranged from a minimum of − 5 (many lesions on the back) to a maximum of 7 (history of exposure to HFMD or herpangina in the last 10 days). The final scores ranged from − 5 to 24 points, with a predictive accuracy of 0.12–0.99. The sensitivity and specificity of the scoring system was 0.76 and 0.62 while the positive predictive value (PPV) and negative predictive value was 0.88 and 0.44. The optimal cutoff score was 7 which meant that a score of 7 or more was suggestive of HFMD while a score <7 could be considered as non-HFMD.[2]

One often comes across atypical presentations of HFMD in practice. These include peculiar morphology (erythema multiforme-like lesions, purpuric lesions, pustular lesions, Gianotti-Crosti-like lesions) as well as distribution (face, scalp, pinna, inner thighs, etc.) (personal observation). These unusual clinical manifestations mimic other viral exanthems and make it difficult to differentiate HFMD from other causes. Newer viral illnesses such as monkey pox which have recently been in the news also have lesions that are similar to or overlap with HFMD. While viral detection by the PCR assay is the gold standard for diagnosis in all these cases, having a validated scoring with a high PPV, in a large sample size like the one in the above study, goes a long way in making rapid diagnosis. Prompt identification of the atypical features of HFMD will also reduce the burden of disease and the outbreak in the community.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1. Kimmis BD, Downing C, Tyring S Hand-foot-and-mouth disease caused by coxsackievirus A6 on the rise Cutis 2018 102 353 6
2. Huang H, Deng L, Jia L, Zhu R A clinical scoring system for pediatric hand-foot-mouth disease BMC Infect Dis 2021 21 722
Copyright: © 2022 Indian Journal of Paediatric Dermatology