White Paper: Modernizing Pediatric Clinical Trials for the 21st Century Cures Act

White Paper

Title: Modernizing Pediatric Clinical Trials for the 21^st Century Cures Act

Marcelo Ramalho-Ortigao, PhD^1,2*, Lynnete Apodaca³

¹Medical and Science Advisor, DIPG Advocacy Group

²Founder, NextGen Consulting LLC, Colorado

³Marc Jr Foundation, Thornton, CO

‍^*To whom all correspondence should be addressed: mrortigao@gmail.com 

________________________________________________________________________________

Clinical trial modernization for diffuse intrinsic pontine glioma (DIPG): a rationale for the use of telehealth

DIPG is the deadliest of all pediatric tumors/cancers and robs patients of every essential motor function, including locomotion, speech, and breathing, while maintaining cognitive functions. The devastating effects of DIPG often prevent patients from qualifying for or being included in clinical trials that advance medical knowledge and that potentially extend life.

Modernizing pediatric clinical trials will accelerate the development of new therapies for DIPG patients and provide hope for an effective treatment to a devastating disease that affects primarily children

For pediatric diffuse midline glioma (DMG) or DIPG in particular the addition of telehealth to clinical trials would:

• remove geographic barriers to participation 
• enhance racial and ethnic participation 
• support recruitment and retention of trial participants
• minimize the adverse consequences of trial participation 

In short, due to the sparsity in cases, telehealth for DIPG clinical trials will promote and facilitate patient participation, increase patient pool/cohort, and provide “hope for a cure” for a disease whose long term survival is practically zero 

The DMG/DIPG pediatric population will significantly benefit from the inclusion of telehealth in clinical trials by reducing stress and the pressures associated with continued travel demands required by current protocols.

The use of telehealth in DIPG pediatric clinical trials will follow a minimum set of criteria set forth the American Telemedicine Association and other professional associations¹

Abstract/Introduction

Diffuse intrinsic pontine glioma (DIPG) or Diffuse Midline Glioma (DMG) as it is currently known, is a high grade glioma (HGG) affecting specifically the pons or brain stem. For all patients, DIPG is a terminal diagnosis. Standard treatment is limited to radiation therapy (RT), which is the only demonstrated “effective” treatment. However, and almost inevitably, tumor and symptoms’ progression typically resume after a few weeks or months following RT. Currently, DIPG long term survival (LTS) is virtually non-existent, and close to 85% of patients, mostly pediatric, succumb to DIPG within the first year following diagnosis². Average survival stands at a meager nine months and less than 1% of patients ever reach five years.

Because of its location DIPG is not amenable to be controlled by surgery, and drug therapy using various molecules or compounds with demonstrated effectiveness in pre-clinical trials, including in vitro studies, is a challenging prospect as drugs must be permeable to the blood brain barrier (BBB). Hence, no effective therapy exists for DIPG, and the first course of treatment, radiation, provides only temporary relief ^2,3. 

In addition, the availability of novel treatments likely has been hampered by multiple factors, including:

• Limited research funds for pediatric cancer with DIPG funds estimated at 0.005% of the total National Cancer Institute (NCI) annual budget;
• Reduced number of cases, with an estimated 400 cases per year in the US (https://dipg.org/dipg-stats/);
• Limited number of clinical trials specific for DIPG
• Lack of successful outcome measured in terms of LTS or progression-free survival (PFS).

The difficulty to effectively deliver potentially life-saving drugs to the tumor, underscored by the need of the drug to cross the BBB, has also negatively contributed to the assessment of novel drugs or drugs already deemed safe for use against pediatric cancers. While novel delivery approaches have demonstrated success, namely convection enhanced delivery or CED, its implementation requires extensive training and it has been limited to a handful of hospitals in the US and Europe. Other potentially effective approaches primarily consisting of easy to administer medications and drugs (e.g., oral pill) that are able to bypass the BBB and reach the tumor must be tested. Modernizing clinical trials to include telehealth will open the possibility of such drugs being tested on a larger scale and with more patients. This will provide critical feedback as to the effectiveness of such therapies in a wider target population, and perhaps bring about the outcome so many of DIPG families yearn for: LTS for their loved ones. Such request for the inclusion of telehealth as an option during DIPG treatment is supported by evidence of the effectiveness of telehealth in treating both adult and pediatric cancer patients^4-6, and is based on our need to modernize several aspects of public health as outlined in the 21^st Century Cures Act⁷

The 21^st Century Cures Act (H.R.6, 114^th Congress) was originally introduced in the House by Rep. Fred Upton (R-MI6) on 19 May 2015 (https://www.congress.gov/bill/114th-congress/house-bill/6/summary/00). Amongst its primary objectives, the 21st Century Cures Act bill amends the Public Health Service Act to reauthorize the National Institutes of Health (NIH), establishes the NIH Innovation Fund, and requires the NIH and the Food and Drug Administration (FDA) to “implement a system that allows further research on clinical trial data”.

In addition, the 21^st Cures Act provides that “[T]he Centers for Disease Control and Prevention must expand surveillance of neurological diseases”, and that “[T]he Council for 21st Century Cures is established to accelerate the discovery, development, and delivery of innovative cures, treatments, and preventive measures”. The law also establishes that “The priority review voucher program for rare pediatric diseases is revised and extended”, that “the FDA must: (1) establish a program for priority review of breakthrough medical devices, (2) identify types of devices that do not require a report preceding introduction, and (3) rely on a third-party to determine the safety and effectiveness of changes to medical devices”.

In our view, the stipulations present in H.R. 6 are highly pertinent to the rationale laid forth in this White Paper for the incorporation of telehealth into pediatric clinical trials aimed at DIPG patients. In addition, here, we outline aspects of the current “state of the art” with regards to therapies, outcomes, and effects of DIPG. Our rationale for implementation of telehealth as a reliable source for both physicians and DIPG patients stems from previous such applications in both pediatrics and adult cancer therapies. DIPG patients who otherwise may not have access to new drugs available in clinical trials due to travel requirements and possibly other disqualifying criteria may benefit from the modernization of clinical trials to include telehealth.  Telehealth in DIPG clinical trials will be a game changer to many patients and families, as well as to data collection by increasing cohorts, and will provide a glimmer of hope for the desperate situation in which DIPG families find themselves while searching for an effective therapy.

DIPG symptoms and current outcomes

Though not restricted to children, DIPG most frequently develops and is diagnosed in the pediatric population between the ages of three and 10 years. Diagnosis is principally confirmed via an MRI of the brain⁸, and DIPG is deemed terminal upon diagnosis. DIPG symptoms range from cranial nerve palsy affecting facial expressions (frequently observed at diagnosis) and progress to affect virtually all neuro-motor functions including but not limited to lower and upper limbs movement, severe ataxia, balance, the ability to stand and/or walking, the ability to communicate verbally (speech), throat movement affecting the ability to swallow, and finally the ability to breath unassisted. Symptoms, however, do not occur necessarily in any particular order and may occur at any time during DIPG tumor progression. 

The progression of DIPG takes an enormous toll on the entire family. Although the patient is severely debilitated, cognitive abilities remain. Moreover, the evolution of severe symptoms vary widely, with some children succumbing to the tumor in a few short weeks (two weeks survival has been reported) while others may continue to fight for the life for a few months to a couple of years. Often, because the patient is unable to move or speak, families—primarily the patient’s parents—and caretakers become completely responsible for providing all the support required, from personal hygiene and feeding, to mobility. DIPG patient care eventually will involve not only caretakers and family, and the physician provider, but also a network of physical and speech therapists, support medicine and mental health staff and providers.

Invariably, families affected by DIPG will embark on one of the most painful undertakings anyone can experience. In addition to DIPG’s significant psychological impact, the financial toll can also be staggering: The cost of searching for therapies typically runs at a minimum at $300,000 per family. Based on current estimates, in the US alone, at least $20 million are spent per year on treatments that at best prolong the life of children for a few weeks to a few months.

Loss of life for pediatric cancer is approximately 70 years. It represents whole generations lost. DIPG average survival is nine months. Today, in the U.S., pediatric cancer is the leading cause of childhood mortality, with DIPG being the most prolific killer of all cancers!

New drugs

Childhood cancer survival has improved significantly over the past decades often thanks to advances first seen in adult oncology. New drugs and therapies are usually first developed for adult patients and may then transition to the pediatric population. Typically, such an approach offers lower toxicity risks to the pediatric patients as dose toxicity can already be identified in the older group. However, in spite of the successes achieved for many pediatric cancers, patient outcomes for those difficult-to-treat diseases, including DIPG, have not really seen many benefits. For DIPG in particular, radiation, the same “effective” approach, has remained the standard therapy for over six decades. Radiation, unfortunately, only provides temporary relief as the tumor generally comes back within a few weeks to a few months.  DIPG’s survival has basically remained unchanged since Neil Armstrong’s daughter Karen (“Muffie”) was diagnosed with DIPG in 1961. In contrast, survival rates for other childhood cancers have gone up significantly. 

Advances in DIPG therapy are extremely challenging for many reasons, including the tumor’s location in the pons (the pontine area of the brain or brainstem) and the limited amount of funding directed for DIPG.  According to the NCI, roughly only 3.9% of its annual budget goes to pediatric cancer as a whole, with an extremely small fraction of that percentage (0.005%) going specifically to DIPG.

Such lack of research funds for DIPG is thought by many to be one of the driving forces impeding the development of new therapeutic approaches, including the search for novel drugs. The lack of research fund increases also appear to go counter the provisions established by the Rare Diseases Act of 2002 (H.R. 4013; 42 USC 201). The Rare Diseases Act of 2002 stipulated an “increase the national investment in the development of diagnostics and treatments for patients with rare diseases and disorders”; and was also aimed towards “amend[ing] the Public Health Service Act to establish an Office of Rare Diseases at the NIH.”

Neither of these two stipulations approved during passage of that bill were ever implemented. As such, an Office of Rare Diseases has never ever been established within the Office of the NIH Director (per the NIH’s own administrative chart), and no increases in the overall percentage of funds towards pediatric cancers has occurred, remaining for the last 40 years or so in the historic 3.8 to 3.9% of the total NCI budget.

Rare diseases are defined as “diseases and disorders that affect small patient populations, typically populations are smaller than 200,000 individuals in the United States”.  Accordingly, all pediatric cancers are classified as rare. In spite of increases in the NCI budget subsequent to the Rare Diseases Act of 2002, no change in the overall percentage of funds towards pediatric cancers have been observed. Further, DIPG, due to what is unfortunately considered “rarity” in the U.S. pediatric population, remains at the bottom of the list as far as research and treatment funding.

In spite of the severe funding shortage plaguing the DIPG community,  a handful of preclinical studies mostly funded via private donations, are offering new hope to our children. New drugs, primarily small molecules that are able to cross the BBB and reach the pons region of the brain, have been tested with some level of success in animal models^9,10. Some of these molecules have shown promise against other forms of HGG, including midline HGG or neuroblastoma^10-12. The identification of DIPG markers and their association with the likelihood of success for a particular drug has also been established^10,13,14. One of the most prominent drugs being used, ONC201, is the first in its class of imipridones¹⁵. Chemically, ONC201 is defined as 7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo [1,2-a]pyrido [3,4-e]pyrimidin-5(1H)-one compound that specifically leads tumor cells to undergo apoptosis (cell death) through the activation of apoptotic cellular pathways induced by various immunomodulatory mechanisms¹⁵.

Recently, the application of novel approaches such as chimeric antigen receptor T-cells, or CAR-T, under investigative therapies (clinical trials phases 1a and 1b) have been shown significant improvement in a handful of patients who have been lucky enough to the be deemed eligible for such trials. CAR-T approaches are limited to a handful of hospitals and clinical centers across the country and not every patient has benefitted for this intervention. Nevertheless, the transient success achieved demonstrate that DIPG can be a treatable disease if it gets the attention it deserves.

Clinical trials:

Clinical trials (CTs) are generally run in a handful of hospitals and coordinated by a sponsor or drug manufacturer. Strict rules regulate CTs whose design and specific protocol is pre-approved by an independent institutional review board (IRB). In the US, the FDA is responsible for overseeing all clinical trials making sure all are in compliance with current law and federal regulations. Further details on the FDA regulations can be found on the website: https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/institutional-review-boards-irbs-and-protection-human-subjects-clinical-trials.

By definition, CTs are data driven and devised to collect as much relevant information of the effects of a particular drug or treatment in regards to its effectiveness, or lack thereof, on a particular disease. Each clinical trial must also assess each patient’s response to the drug or treatment being investigated. For reasons that will not be discussed here, patients will respond differently to the same trial or drug. Hence, the collection of all pertinent data from each patient includes: blood and urine analyses to assess bioavailability, pharmacokinetics, and markers of treatment success; tissue and tumor samples obtained from biopsies, to identify individual genetic and cellular markers that are or can be associated with outcome; physical examination prior to, during , and after (if required) the trial.

To date, a limited number of drugs or small molecules have been tested specifically against DIPG in various CTs (https://www.science.gov/topicpages/p/pontine+gliomas+dipg.html). Due to the documented dismal survival among DIPG patients, if and when a drug or compound shows any promise of LTS for DIPG, it, unsurprisingly, provokes a ripple effect in the DIPG community, enticing providers, along with parents and caretakers to submit DIPG patients to such treatment. Selection, availability, and qualification to a clinical trial is dependent on many variables (https://www.cancer.gov/news-events/cancer-currents-blog/2019/expanding-clinical-trial-eligibility-criteria). However, it is clear to physicians, scientists, and especially patients and families that pediatric cancer clinical trials must be more inclusive¹⁶.

Any investigational new drug (IND) that shows promise or may represent a sliver of hope to DIPG patients and families can be made available outside CTs. However, the availability of such drugs, possibly under expanded use protocols regulated by the FDA (https://www.fda.gov/media/85675/download), is sparse. Nevertheless, fundraising and advocacy efforts from private foundations have recently resulted in certain drugs becoming available under extended use or compassionate use protocols (see “The role of private foundations” below). Parents, families, and a patient’s guardian(s) will go to any lengths to procure such drug, including signing on to CTs that are often only found hundreds and sometimes thousands of miles from their home base: traveling to a specialized DIPG or pediatric tumor center is typically the norm for DIPG patients and families. Though often a great burden (financially, physically, and often emotional) such a sacrifice pales in comparison to what we as families and parents are willing to go through for our children. However, as we have often witnessed, to remain eligible for a clinical trial and the continuation of care associated with such trial, patients and their families or care takers have to return multiple times to the center in which they enrolled for follow-ups required by the study protocol. Non-compliance to the protocol represents grounds for ineligibility and removal from the clinical trial. As indicated above, guidelines for CTs are, with reason, strict and enforced by the FDA.

Overall, it is estimated that more than 200 clinical trials focused on DIPG have been completed in the last 10 years (https://thecurestartsnow.org/). As of May 2020, 69 trials across 16 countries specifically targeting new therapies and approaches for DIPG were ongoing (https://dipg.org/dipg-treatment/active-clinical-trials/).  Since then, the number of CTs available has jumped slightly to a current total of 79 CTs in 19 countries (as of 21 January 2022). However, such an increase in trial availability does not necessarily represent huge advances in terms of effective therapies against DIPG. According to The Cure Starts Now (TCSN), the largest advocacy and funding private foundation in support of DIPG, DIPG clinical trials have suffered from exclusion rates, which are viewed among DIPG advocacy groups as too high. DIPG clinical trials exclusion rates will remove roughly 50% of patients seeking to advance medical knowledge to support new therapies and perhaps an extension of their estimated life expectancy (DIPG LTS is only 1% after 2 years). They are too often denied the opportunity to participate in the trials, and by extension the promise of such novel interventions. The high exclusion rates also include families and patients unable to reach treatment centers due to factors such as financial constraints or distance to these centers. 

In addition to the despair provoked by exclusion from a potentially life-saving or life-extending drug trial, the issue of attrition also becomes a matter of statistical relevance.  Recent studies suggest that a minimum of 27 patients are necessary to assess the effectiveness of DIPG drug treatments. From information collected from TCSN and The Collaborative Network for Neuro-oncology Clinical Trials (CONNECT), a minimum of 3699 DIPG patients is needed just to cover the trials funded by TCSN. This is based on the number of DIPG cases in the past 10 years and the 137 clinical trials directly funded by TCSN (of the 200 total estimated trials run in the same period). However, based on current estimates of 300 to 400 cases of DIPG per year in the U.S., not enough DIPG patients exist (or survive) to fill CT enrolment under current trial designs.

Hence, while trials conducted in the U.S. are generally larger than in other countries the potential attrition or dropout rate that all trials exhibit is not the only factor affecting accrual of meaningful data. The real problem is the accrual of patients. Current exclusionary rates of patients who may either be oligosymptomatic and/or with a low combined Karnofsky score reach nearly 50%. Such high exclusion rates means the accrual rate is likely a bigger issue than generally perceived.

Telehealth: The Basics

Telehealth: Definitions and Applications

There are many definitions of telehealth used by federal and state regulators, medical societies, as well as public health programs and commercial health insurance plans. For the purpose of this white paper, we are defining the terms telehealth and telemedicine in the following manner:

• Telemedicine.  The American Academy of Pediatrics (AAP) defines telemedicine as the “the use of medical information exchanged from one site to another via electronic communications to improve a patient’s clinical health status.”¹⁷. The term “telemedicine” is typically limited to the use of these technologies when a provider delivers direct patient health services. 
• Telehealth. The term “telehealth,” often used interchangeably with telemedicine, is used in this white paper as a broader term that includes telemedicine, as well as other health related services using electronic information and communications technologies, such as health information sharing, health profession and patient education, and remote or mobile patient monitoring.

The ability to remotely access patients has been around for many years, and telemedicine provides patients and providers the opportunity to communicate and interact in a meaningful way that would not otherwise be possible. For instance, patients who live in rural areas are underserved and may lack access to advanced treatment and diagnostics in their local community, and providers in such academic research centers are often unable to reach out to rural communities. However, in many instances, telemedicine was limited to what it could provide with regards to exams and analyses, directly affecting treatment and possibly outcome. Recent advances, however, have allowed for more extensive interactions between patients and providers trough remote monitoring ^17-20. Telemedicine and telehealth have been effectively used to provide access and to address shortages of physician workforce⁶. Specifically in regards to cancer, previous studies have suggested a benefit from telehealth²¹. Moreover, such the benefits were clearly extended to clinical trials for adult patients¹⁹, and revealed that out of 217 patients, with 134 rural and 83 urban, 95% indicated “their telemedicine visit was better that an in-person visit”.  

‍Telehealth: COVID-19 Seismic Transformation of Healthcare Delivery

In a historic and unprecedented expansion in the history of healthcare has provided much needed access to treatment in times of severe shortage and risk associated with providing in-person care due to the coronavirus pandemic (https://www.hhs.gov/coronavirus/telehealth/index.html).

Telehealth: Clinical Literature 

Recently, a comprehensive systematic review on the benefits of telehealth has recently become available²² (https://www.ncbi.nlm.nih.gov/books/NBK547241/). The review summarizes the available evidence about the effectiveness of telehealth consultations. After assessing one thousand articles from an original list of over 9000 potentially relevant publications, 233 studies met the criteria for telehealth, according to the study’s authors²². Selected telehealth studies focused on prevention, assessment, diagnosis, and/or clinical management of acute or chronic conditions included 54 cases of inpatient consultations; 73, emergency care; and 106, outpatient care. Though overall results varied according to setting and clinical topic, overall telehealth improved outcomes or no difference between telehealth and non-telehealth approaches were reported. In addition, for intensive care unit (ICU) needs, remote consultations likely reduce ICU and total hospital mortality with no significant difference in ICU or hospital length of stay; specialty telehealth consultations likely reduce the time patients spend in the emergency department; telehealth for emergency medical services likely reduces mortality for patients with heart attacks; and remote consultations for outpatient care likely improve access and a range of clinical outcomes (moderate strength of evidence in favor of telehealth). Other findings indicated that inpatient telehealth consultations may reduce length of stay and costs; telehealth consultations in emergency care may improve outcomes and reduce costs due to fewer transfers, and also may reduce outpatient visits and costs due to less travel (low strength of evidence in favor of telehealth). The increase in both interest and investment in telehealth suggests the need to develop a research agenda that emphasizes rigor and focuses on standardized outcome comparisons that can inform policy and practice decisions. Significant additional information regarding the various benefits brought to bear by telehealth/telemedicine can also be found in the Health Resources & Services Administration (HRSA) website (https://www.hrsa.gov/rural-health/telehealth), and in the National Quality Forum (NQF, http://www.qualityforum.org/Home.aspx). Irrespective of the analysis, it is abundantly clear that the use of telemedicine and telehealth has been extremely effective in providing patients with high quality medical care access and help address shortages of physician workforce⁶. According to the Patient-Centered Outcomes Research Institute (PCORI), “there is a growing sense that telehealth can help people manage their health and improve their access to care, especially in areas where health professionals and facilities are sparse, or when circumstances make it difficult for them to travel to their healthcare providers” (https://www.pcori.org/collection/telehealth-highlights-pcori-funded-research-studies). Currently, studies funded by PCORI seek to determine specific benefits for patients enrolled in telehealth approaches. PCORI’s research portfolio is testing telehealth across a wide spectrum of conditions, including heart disease and stroke, nutritional and metabolic disorders such as diabetes and obesity, and mental and behavioral health. The studies—tailored to patients’ goals and preferences—most frequently assess patient well-being, health behaviors, and treatment outcomes. The data to date clearly points to the benefits of telehealth across many medical conditions, including some pediatric cancers (https://www.pcori.org/research-results/pcori-stories/can-telehealth-improve-care).

Telehealth: Coverage and Reimbursement

According to the American Association of Telemedicine (ATA) 2019 State of The State Report telehealth coverage and associated reimbursement:

• 40 states and the District of Columbia (D.C.) have adopted substantive policies or received awards to expand telehealth coverage and reimbursement since 2017.
• 36 states and D.C. have parity policies for private payer coverage; only 21 states and D.C. have coverage parity policies in Medicaid.
• 28 states have Medicaid payment parity policies; only 16 mandate payment parity for private payers.
• The majority of states have no restrictions around eligible provider types; ten states have authorized six or more types of providers to treat patients through telehealth.
• Only 16 states limit telehealth to synchronous technologies while most of the country recognizes the benefits of remote patient monitoring (RPM) and store and forward (S&F).

‍Telehealth: 21^st Century Cures Act Modernization

Telehealth is already inexorably connected to the modernization efforts set forth by the 21^st Century Cures Act (Cures Act), which was signed into law on 13 December 2016. The Cures Act was designed to “help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently”. Plus, the Act allocated substantial support to the US Food and Drug Administration (FDA) in order to streamline the process for drug and medical device approvals, promote increased use of electronic health records, eliminate bureaucratic red tape, and advance the implementation of telehealth services

Telehealth: Delivery Platforms

The advent of new systems allowing for additional interactions between patients and providers now offer the possibility of full patient assessment via remote connection. Several such systems and platforms are currently available, including Medpod® (Medpod Inc., Henry Schein), which is designed to provide telediagnostics associated with acute, sub-acute, urgent, and ambulatory care of patients from a remote location. This system complies with federal and local guidelines, particularly those from the FDA. Another, named The Network of Network Oriented Research Assistant (NORA), a platform developed by Boehringer Ingelheim allows the researcher to interact with patients “through the direct capture of data with automatic integration to another electronic data capture system”, and according to its developers “allowing for more real-time access to, and monitoring of, the data being collected within a clinical trial”. Under its current license, the NORA platform arguably permits significant oversight of the clinical trial being conducted. 

Telehealth: Clinical Trial Reform Partners

Moving forward with the application of telehealth towards DIPG trials will require the participation of various professional associations, including The American Telemedicine Association, The American Society of Pediatric Hematology/Oncology, and the AAP, in combination with the FDA as the primary regulatory agency, and DIPG advocacy groups such as TCSN, The Michael Mosier Defeat DIPG Foundation, and the MarcJr Foundation, among others. The implementation of telehealth for DIPG treatment will abide by the rules and regulations set forth by the American Telehealth Association¹ and other professional organizations, and will conform to state and local regulations, and FDA requirements.

Telehealth: Impediments to Use for Clinical Trials in State and Federal Laws 

Although telemedicine platforms have evolved considerably and have been used during conventional treatment regimens providing access to underserved rural communities, implementation of telemedicine in CT has not kept up pace. 

Many reasons exist for such discrepancies, including federal and state laws that govern the use of technology when delivering medical services.   These laws govern research, regulation, payment and coverage, liability, and interoperability. At the state level one of the most challenging has been the role of state licensure of researcher/clinicians where participants reside in a number of states. Differences in licensure and telehealth specific laws across states have created roadblocks for the implementation of telemedicine in clinical trials. Additional information pertaining to current state and federal regulation as well as marked differences between them with regards to telehealth, the reader is encouraged to visit: http://connectwithcare.org; http://telehealth.hhs.gov and; https://www.cchpca.org.

Although CT regulations fall under the FDA, there is not a simple solution to the issues of state telemedicine laws as state laws have to be addressed and the FDA does not have authority to preempt these laws. Until federal and state laws can address this issue, in the interim one solution involves communicating directly with the FDA and with state medical and pharmacy boards (where appropriate), and when necessary, obtain waivers from the FDA and the applicable licensing boards. More importantly, it is our view that FDA regulations and guidelines pertaining to clinical trials should evolve as technology evolves. 

Making clinical trials for DIPG patient flexible and humane

The modernization of CT for DIPG patients will, to some extent, bring a new hope to families that are undergoing the severe trauma of watching their loved ones, primarily children, go through the ravages of DIPG. It is difficult enough for parents and/or care givers to assist a child daily with every single routine. Compound this with the fact that DIPG patients are unable to move and/or speak, while fully cognizant of their surroundings. The current lack of effective therapy for DIPG and the fact that a very limited number of drugs and treatments are, at any given time, tested against DIPG point to a single reality: the stakes for DIPG could not be higher.

Another very important facet of the DIPG treatment has to do with the limited availability of centers capable of dealing with the disease. Thus, travel is often required in search of adequate treatment, which can add an extra burden: financial. Many families also are willing to travel internationally in search of any treatment that hold the promise of life extension or cure, even if without scientific merit or support from advocacy groups, scientists and or physicians in the US. However, who can blame parents from trying every possible way to save their children’s lives?

This current reality makes selection of clinical trials difficult. In addition, for clinical trials, the rate of success is often dependent on the specific molecular signature of a tumor, i.e., tumors carrying specific mutations may respond more or less to a particular drug. Specific DNA mutations have been identified and associated with positive outcomes¹³ and should be taken into consideration when designing clinical trials or designing tailored drug interventions. For DIPG in particular, LTS has been associated with the presence of a methionine (M) amino acid residue instead of a lysine (K) in position 27 of the histone H3.1 gene histone (HIST1H3B-H3.1 K27M)¹³.

In general, DIPG retrospective studies do not specifically detail the physical condition presented by their cohort (e.g., able to travel, or no ataxia, or other condition deemed as an impediment to safe/comfortable travel). Often, prior to a clinical trial the patient’s physical condition must be assessed by various metrics such as the Karnofsky Performance Status^23,24 (KPS). Depending on the results of the physical assessment, it can be disqualifying. For a DIPG patient, travel to a clinical trial site, though potentially perceived by medical personnel as a “simple event” can be extremely onerous, both in terms of associated costs but also for the sake of the child/patient overall physical status. However, a clear linkage from the experiences detailed in such studies to the physical limitations faced by DIPG patients, specifically children, is not possible. Without a doubt, telehealth has the potential for providing a positive impact across our DIPG community by offering access to care to an otherwise likely underserved population regarding their oncology care needs.

As indicated earlier, there are currently 69 trials across 16 countries targeting DIPG (https://dipg.org/dipg-treatment/active-clinical-trials/). In addition to providing access to novel drugs and therapeutic approaches, the inclusion of telehealth for DIPG clinical trials may also facilitate the inclusion of drugs already deemed safe for children as potential therapies for DIPG. The current completely unfavorable outcomes that all DIPG cases ultimately face begs the question as to why there are no more options or inventive solutions. The status quo is clearly unacceptable for all of us. Telehealth is a proven effective approach with documented success at many levels. Nine months survival is not a viable option, and we must have more to offer. Telehealth can bring additional experts into the reach of DIPG patients and families who yearn for a solution better than what is currently available.  To think that the therapy that is widely accepted as the “only [partially] effective approach” is the same therapy used in the early 1960’s, and without any practical long term benefit to DIPG patients is or should be the norm is unacceptable. Flexibilizing DIPG clinical trials with telehealth making new drugs and therapies available to all those who need while offering the convenience of the remote access will provide the means for new advances.

According to AnjuSoftWare’s “Strategies to Maximize Retention in Trials” (https://www.anjusoftware.com/about/all-news/insights/rare-disease-clinical-trials), the flexibility or “patient-centricity” we advocate for DIPG clinical trials is not just a buzzword but a real necessity to keep patients enrolled in rare disease trials. Patient-centricity is a new paradigm that requires understanding the burden the study will place on patients and how to lighten it. Clearly, it also requires determining the appropriate endpoints and satisfying patients with the quality of treatment and care they receive. With this new paradigm in mind we can, where possible, reduce the number of site visits by sending medication and homecare health practitioners to patients’ homes. Further, drug infusions, blood draws, PK sampling and minimally-invasive tests could be carried out either at home or a care facility closer to home instead of requiring the patients to attend a much more distant site where the clinical trial is being conducted. This would represent a leap in our approach to DIPG trials that will surely be met with praise throughout the DIPG community.

However, it is also important to realize that strategies for patient-centricity include a comprehensive risk/benefit profile and a clear consent form — perhaps in video format, which can be especially helpful for making procedures clear to pediatric patients. Also important but often forgotten is the duty of trial staff to provide comfort through helping patients access support network, counselling and organizing transport to advocacy meetings.

‍The role of private foundations

Many private foundations today are responsible for the bulk of the research funds going to DIPG. Moreover, some of the same foundations have been responsible for organizing the network of pediatric oncologists and scientists that having been at the core of the information dissemination regarding DIPG. Advances in gene sequence, specifically the next generation sequencing (NGS) platforms currently available have provided crucial data regarding the genomic fingerprint of specific DIPG tumors and patients. Targeted therapy for DIPG is now in the horizon and specific success of particular drugs have already been associated with specific genetic markers present in certain DIPG tumors^25,26. 

Many such advances owe to the commitment of these foundations and the donors that have supported them. One such example comes from one DIPG organization, The Cure Starts Now (TCSN). Through its network of funders, TCSN has raised over $14 million for cancer research, resulting in 90+ grants for cutting edge research (both basic and clinical) in 15 countries since 2007. Significant amounts of money have also been raised by many other DIPG advocacy groups, and the vast majority of such funds go directly to support research, novel treatments, support care, and many other activities directly associated with the well-being of DIPG patients and their families. 

We estimate that, in the last 10 years, there have been nearly 200 clinical trials focused on DIPG patients and potential effective drugs and other therapies (according to data from TCSN) with the majority of the funding coming from private donations and DIPG advocacy groups. Unfortunately, federal funding for DIPG stands at approximately 0.005% of the entire budget for the NCI, with all pediatric cancers receiving 3.9% of NCI’s budget. Under such funding landscape, one striking statistics remain: not a single pediatric tumor drug or treatment has been approved for DIPG, and the same approach used in 1962 to treat Neil Armstrong’s daughter Karen “Muffie” Armstrong, radiation therapy, remains the only option but only providing temporary relief.

The DIPG landscape is surely a difficult one for any family affected by this terrible disease to navigate. However, the determination and strength many families have demonstrated after having a loved one suffer the consequences of DIPG and having to say goodbye to their children at such a young age, gives hope that a cure of a successful treatment will be identified and DIPG will no longer be a death sentence. As parents of children who succumbed to DIPG, and as members of the DIPG community we will continue our fight for additional funds and for novel discoveries that may one day change the current fate of our children affected by this relentless disease. We owe this fight to our children!

‍In support of the telehealth approach for pediatric cancers

During the crafting of early versions of this White Paper, a meeting focused on current DIPG research developments and treatments options was held on 13 February 2020 at the Covington LLP law offices in Washington, DC.  The “State of DIPG Meeting” brought together physicians, scientists, advocacy groups, patients and families to discuss past and current approaches to treat DIPG, and well as what the path forward may look like with regards to the development of new therapies and how to expand access to such therapies to DIPG patients. Among the many presenters, Dr Gregory Reaman, Associate Director in the Office of Hematology and Oncology Products, discussed issues relevant to clinical trials access and regulations. Dr Reaman stated that “we should not expect families to travel long distances for clinical trials”, and “there must be a better way we can serve people who need access”. Clearly, the statements from Dr Reaman (though not necessarily the official position of the FDA) go right to the core of what is being proposed here, whereas the incorporation of options (i.e., flexibilization of current regulations regarding trial eligibility and CT continuation) for DIPG patients can bring about life-saving or the very least life-extending opportunities for all of us who suffer severely from the lack of effective therapies. The inclusion of more flexible approaches, i.e., telehealth to pediatric trials for DIPG, shall provide the opportunity for patients to qualify and be included in such studies. For many of us, been disqualified from a clinical trial due to travel requirements often just related to follow up clinical examinations should be unconscionable and this must be improved. Telehealth offers such possibility.

‍Conclusion

DIPG is the deadliest pediatric tumor affecting hundreds of children in the US alone, but the current pace of drug discovery for pediatric tumors has not kept with our pace of development in other areas of medicine. No effective treatment exists and radiation, the only reliable therapy since the 1960’s, only provides temporary relief. Sadly, virtually nothing has changed from the days “Muffie” Armstrong was diagnosed and then underwent radiation therapy for DIPG. “Muffie” passed away in 1962 as Mr. Armstrong and other American heroes engaged in the Moonshot Program set forth by then President Kennedy. In the spirit of that program, the DIPG Advocacy group, which represents DIPG families and patients across the country is currently fighting for the approval in the US Congress of House Resolution (under the 116^th Congress, this resolution was identified as to H. Res 114) which shall designate May 17 as “DIPG Awareness Day”. It is expected that with increased awareness, an increase in DIPG research funds will follow. Unfortunately for the families afflicted by DIPG, this disease feels more like a neglected disease than a rare tumor: the only rare aspect to DIPG is that it is rarely talked about. Of the many issues stacked up against DIPG patients, access to clinical trial and the possibility of a life-extending therapy should not be one of those issues. Opening up DIPG clinical trials to remote access through currently available telehealth platforms will, without a doubt, increase the representation in such trials and likely speed up the process to drug/therapy development.

Acknowledgements

The authors would like to express their gratitude to many people involved in DIPG advocacy and who have directly or indirectly contributed to the ideas presented in this white paper, especially Janet Demeter (Jack’s Angels and DIPG Advocacy Group), Gerry Tye (DIPG Advocacy, Australia), Joseph Medina (Marc Jr Foundation), and Sylvia Trujillo for their comments and suggestions during the writing of this white paper.

‍Disclosure

During the crafting of earlier versions of this White Paper, Dr. Ramalho-Ortigao served as Professor of Preventive Medicine and of Emerging Infectious Diseases in the Department of Preventive Medicine and Biostatistics at the Uniformed Services University. Dr. Ramalho-Ortigao contributed to this article in his personal capacity and is no longer associated with USU or the Federal Government. Authors have no competing interests with regards to the issues described herein. Both Dr. Ramalho-Ortigao and Mrs. Apodaca are surviving parents of children who passed away from DIPG. Both the DIPG Advocacy Group and the Marc Jr Foundation are not for profit institutions aimed at improving the lives of DIPG patients. 

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