Infliximab for the treatment of paediatric Crohn's disease: Obstacles to accessing a necessary therapy

The inflammatory bowel diseases (IBDs), comprising Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic chronic relapsing disorders of the gastrointestinal tract. Up to 25% of cases present during childhood and adolescence (1) and are associated with significant morbidity as manifested by debilitating symptoms, frequent hospitalizations, growth retardation and need for surgical interventions (2–6). Unfortunately, there is currently no cure (except at the cost of total colectomy and permanent ileostomy in UC) (7), and no single therapy is effective in controlling disease in all patients. As such, current therapeutic goals are directed at inducing remission during exacerbations and maintaining remission during quiescence while minimizing therapeutic side effects (8). Recent advances in our understanding of the underlying pathophysiology of IBDs have contributed to the development of novel pharmaceutical therapies for these disorders. Infliximab, a chimeric antibody targeted against tumour necrosis factor alpha, a key component in the inflammatory cascade, is one of the most recent therapies that has been proven to be efficacious in the treatment of CD (9,10). Unfortunately, numerous obstacles are encountered in obtaining access to this medication for paediatric patients who have failed multiple IBD therapies. These obstacles are not unique to paediatric patients with IBD but represent important issues facing the Canadian health care system's ability to deliver appropriate care to our youth. As paediatricians and paediatric gastroenterologists, we believed it was important to highlight these issues (using infliximab as an example) to serve as a discussion point (Table 1). Obstacles to accessing infliximab therapy for children with Crohn's disease ‘Off-label’ – infliximab is not labelled for use in patients under 18 years of age Cost – infliximab is extremely costly, and even with drug benefit plans, it may be prohibitively expensive for some families Intravenous route of administraton – requires appropriate equipment and monitoring for administration, either in a health care facility or at a freestanding infusion clinic ○ if at a freestanding infusion clinic, there are concerns about safety and preparedness to deal with paediatric emergencies ‘Off-label’ – infliximab is not labelled for use in patients under 18 years of age Cost – infliximab is extremely costly, and even with drug benefit plans, it may be prohibitively expensive for some families Intravenous route of administraton – requires appropriate equipment and monitoring for administration, either in a health care facility or at a freestanding infusion clinic ○ if at a freestanding infusion clinic, there are concerns about safety and preparedness to deal with paediatric emergencies Obstacles to accessing infliximab therapy for children with Crohn's disease ‘Off-label’ – infliximab is not labelled for use in patients under 18 years of age Cost – infliximab is extremely costly, and even with drug benefit plans, it may be prohibitively expensive for some families Intravenous route of administraton – requires appropriate equipment and monitoring for administration, either in a health care facility or at a freestanding infusion clinic ○ if at a freestanding infusion clinic, there are concerns about safety and preparedness to deal with paediatric emergencies ‘Off-label’ – infliximab is not labelled for use in patients under 18 years of age Cost – infliximab is extremely costly, and even with drug benefit plans, it may be prohibitively expensive for some families Intravenous route of administraton – requires appropriate equipment and monitoring for administration, either in a health care facility or at a freestanding infusion clinic ○ if at a freestanding infusion clinic, there are concerns about safety and preparedness to deal with paediatric emergencies Most patients will initially attempt to obtain access to infliximab in the ambulatory setting through the family's private drug plan. This may present several problems. First, many requests are denied under the premise that infliximab is not labelled for use in Canada for patients younger than 18 years of age. Licensed medications prescribed outside their license are considered ‘off-label’ (11). The use of ‘off-label’ pharmaceuticals is a common practice in paediatrics. A recent supplement to Paediatrics & Child Health reporting on prescription medicine use by one million Canadian children documented the widespread use of off-label pharmaceuticals in paediatrics (12). Studies have shown that up to 70% of medications used in neonatology (11) and 50% of medications prescribed in a paediatric gastroen-terology unit to children discharged to the community (11) are ‘off-label’. According to the 2003 Compendium of Pharmaceuticals and Specialities by the Canadian Pharmacists Association (13), the only drugs approved for the treatment of IBD in Canadian children are corticos-teroids in short courses and the oldest 5-aminosalicylic acid compound, sulfasalazine. Other drugs commonly used by paediatric gastroenterologists to treat IBD, such as the remaining 5-aminosalicylic acid compounds, other corticosteroid preparations, azathioprine, 6-mercaptopurine and methotrexate, are not approved for use in children (12). In spite of this lack of approval, private drug plans do not deny access to these cheaper medications. The prescription of ‘off-label’ medications is necessary in paediatrics because there is often no alternative; approximately 75% of the drugs licensed since the early 1970s have been approved without labelling for use in children (14). Failure of governmental regulatory bodies to ensure that appropriately designed and conducted studies (prospective, randomized, double-blind and placebo-controlled) occur in children has contributed to this situation. For infliximab, and many other medications, use in children is predicated upon extrapolation of data from adult trials and less rigorous sources, including case series and retrospective cohort studies (15–18). The failure to conduct clinical drug trials in paediatrics has been and remains a major roadblock to a reduction in the number of ‘off-label’ medications (19). It also represents a significant impediment to providing appropriate medical care to our children. With limited data on which to base the paediatric risk assessment, the paediatrician is at a distinct disadvantage when discussing with patients and their families the potential risks of this therapy. Although paediatric data are lacking, there are well-recognized safety issues associated with the use of infliximab in adults (20–23). Determined in multiple clinical trials, these include acute infusion reactions, serum-sickness reactions, and an increased susceptibility to infection and sepsis (20). Postmarketing surveillance has shown the development of malignancy, demyelination, congestive heart failure and autoimmune disorders in a small number of patients (22,23). Fatalities from overwhelming tuberculosis infection have also been described in patients receiving infliximab, and have resulted in recommendations for careful screening for this organism before initiation of infliximab therapy (24,25). To date, no adverse reactions specific to children receiving infliximab have been documented in the literature. Unfortunately, although postmarketing surveillance is being conducted, it is not mandatory. Thus, we may not have the whole picture of the true incidence and nature of adverse reactions for both adults and children. This is an area where governmental regulatory bodies can exert pressure on pharmaceutical companies to conduct active post-marketing surveillance of these biological agents. Fortunately, some inroads have been made in the United States over the past few years, and these are highlighted in the recent passage by the United States Congress of S 650, the “Pediatric Research Equity Act of 2003” (26). This legislation will provide the Food and Drug Administration with “additional authority to require paediatric studies of pharmaceutical products when such studies are needed to ensure the safe and effective use of the products in children” (27). Unfortunately, equivalent Canadian legislation is lacking and because health care professionals are entrusted with providing medical care to our children, it is our responsibility to advocate the formation of appropriate legislation. The information obtained from adequately funded multicentre paediatric drug trials will provide urgently needed information on drug efficacy and safety in children with chronic disease. This will also assist paediatricians in the development of guidelines for the use of these expensive medications in appropriate patients. The Canadian government needs to fund these studies or mandate funding from the drug industry. A second hurdle encountered when dealing with private drug plans stems from the significant cost associated with this therapy. When infliximab (Remicade, Schering Canada Inc, Canada) first came on the market in Canada for the treatment of CD on June 6, 2001, it had a list price of $1,150 per vial. As of April 1, 2003, the list price of Remicade has been reduced to $940 per vial, still a significant expense. Because a single infusion for an adolescent may require three to four vials, and the currently recommended induction regimen involves a series of three separate infusions (28), the cost for an induction regimen is between $8,000 to $11,000. Some patients require repeat infusions up to every eight weeks to maintain remission (29), further escalating the annual cost. Without a drug plan, the cost of infliximab would be prohibitive for most patients. Even with a drug plan, financial hurdles may still exist. Most plans require co-payment, and if this is calculated as a percentage of the drug cost, it can amount to several hundred dollars per infusion. Additionally, some plans require the policyholder to pay for the medication up front, obtaining reimbursement on submission of the receipts. This is often not feasible for many patients. For IBD, infliximab is indicated in the treatment of severe active CD in adult patients who have failed to respond to an adequate course of therapy with corticosteroids and/or immunosuppressants (13). It is also indicated for the treatment of fistulizing CD in adult patients who have not responded to an adequate course of conventional therapy (13). In Canada, infliximab has not been labelled for use in children (13). As always, use of any therapy should come after appropriate consideration of the risks and benefits to the individual. The Canadian Association of Gastroenterology has developed evidence-based guidelines for the use of infliximab (30). However, no reference is made in this document for its use in paediatric patients, due in large part to the lack of studies in this patient population. Rational use of these agents is paramount for many reasons. The children and adolescents who are being treated today will have many years to live with their disease. Many of the private drug plans have lifetime maximums associated with them, which will be all too quickly reached when expensive medications are necessary. In the case of group plans, the use of expensive therapies leads to rate increases and/or results in the establishment of restrictions on access by members. Another obstacle to obtaining access to infliximab relates to its route of administration as an intravenous infusion. When infliximab was first introduced, many private insurers ruled that they would not pay for the drug because intravenous infusion required in-hospital delivery, and as such, was an insured service that should be covered by the provincial health care plan. Regional health authorities and provincial health care plans have refused to cover drug costs because children can receive these therapies as ambulatory patients and the costs should be covered by private insurance drug plans. While some private drug plans have since granted coverage for infliximab infusions given in the hospital's ambulatory care clinic, many still deny coverage under this circumstance. For this reason, and because the demand exists, private infusion clinics have opened in many provinces. This practice presents a number of safety concerns. Infusion reactions, including anaphylaxis, are one of the primary risks associated with the administration of infliximab (20). Importantly, unlike in the hospital setting, infusion clinics may not be equipped to handle emergency situations occurring in children ranging from toddlers to adolescents. Unfortunately, in denying coverage for infusions given in hospital outpatient settings, many patients choose to attend private infusion clinics where the ability to handle paediatric emergencies may be dangerously inadequate. Recent advances in medical knowledge have lead to a proliferation in the development of promising novel pharmaceuticals that have improved our ability to treat many debilitating chronic diseases. However, such therapies are often very expensive and raise many challenges to the physician in obtaining access for their patients. All too often, these obstacles result in significant delays to initiating necessary therapies, adding to the suffering incurred by these patients. Physician time is wasted in dealing with multiple levels of bureaucracy of private drug plans, regional health authorities and provincial health care plans to obtain funding and approval for the use of these effective but very expensive medications. Many of these obstacles are universal to all areas of medicine, but some are unique to paediatric patients. Everyone involved needs to work together to ensure that these obstacles are overcome. Governments must ensure that adequate paediatric studies are conducted on new medications to determine indications, efficacy and safety in the paediatric patient. Furthermore, governments need to provide funding or ensure that private drug plans provide funding for these medications. Pharmaceutical companies must ensure that medications are fairly priced and physicians must use sound judgements when prescribing their therapies. Funding responsibilities must be negotiated between private drug plans, regional health authorities and provincial health care plans. We must always remember that efficacious therapies cannot be effective unless they reach our patients. Paediatricians, paediatric departments, subspecialty associations and the Canadian Paediatric Society need to be active in lobbying for initiatives to ensure effective, safe and appropriately funded drugs for Canadian children.

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