ethical issues and risk/benefit assessment of iron chelation therapy: advances with...

Hemoglobin, 32 (1–2):1–15, (2008)Copyright © Informa Healthcare USA, Inc.ISSN: 0363-0269 print/1532-432X onlineDOI: 10.1080/03630260701726533

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LHEM0363-02691532-432XHemoglobin, Vol. 32, No. 1-2, December 2007: pp. 1–27Hemoglobin

PROCEEDINGS 16TH ICOC

Limassol, Cyprus, October 2006

ETHICAL ISSUES AND RISK/BENEFIT ASSESSMENT OF IRON

CHELATION THERAPY: ADVANCES WITH DEFERIPRONE/

DEFEROXAMINE COMBINATIONS AND CONCERNS ABOUT

THE SAFETY, EFFICACY AND COSTS OF DEFERASIROX

Ethical, Cost, Safety and Efficacy Issues of ChelatorsG.J. Kontoghiorghes

George J. Kontoghiorghes

Postgraduate Research Institute Science, Technology, Environment and Medicine, Limassol, Cyprus

� New developments in the area of iron and other metal metabolism and toxicity and the effectsand uses of chelators have been presented at the 16th International Conference on Chelation(ICOC), Limassol, Cyprus in October 2006. Marketing practices by pharmaceutical companies,contradictory policies by regulatory authorities and ineffective policies by health authorities deprivethousands of thalassemia and other transfused patients of life saving iron chelating drugs and ofefficacious chelation treatments. Thousands of patients were using deferasirox (DFRA) worldwide afew months after the European Union (EU) authorities, and about 1 year after the Food and DrugsAdministration (FDA), proceeded to its accelerated approval with no sufficient evidence that thedrug was efficacious, especially for clearing excess cardiac iron, and also safe.

Cases of fatal, acute, irreversible renal and liver failure, fatal agranulocytosis and other toxic-ities have recently been reported with DFRA. The FDA has not yet approved deferiprone (L1) depriv-ing thousands of patients of potentially life saving treatment. The high cost of DFRA at 60 euros/g,L1 at 5.5 euros/g and deferoxamine (DFO) at 8.3 euros/g, diminishes the prospects of universalchelation therapy, especially for patients in developing countries. The safety and efficacy record ofL1, DFO, and their combination in particular, appear to provide universal solutions in the treat-ment of transfusional iron overload, and also in reducing mortality because of their ability to clearrapidly and effectively excess cardiac iron.

Keywords Agranulocytosis, Chelation therapy, Deferasirox (DFRA), Deferiprone (L1),Deferoxamine (DFO), Transfusional iron overload, Thalassemia, Toxicity

Presented at the 16th International Conference on Chelation, Limassol, Cyprus, October 25–31, 2006.Address correspondence to Dr. George J. Kontoghiorghes, Postgraduate Research Institute

Science, Technology, Environment and Medicine, 3 Ammochostou Street, Limassol, Cyprus; Tel.:+35725734615; Fax: +35725395926; E-mail: [email protected]

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2 G.J. Kontoghiorghes

INTRODUCTION

New developments in the area of chelator and metal biological sciences,including therapeutic applications, metabolism, pharmacology and toxicologyhave been presented at the 16th International Conference on Chelation(ICOC) for the treatment of thalassemia, cancer and other diseasesrelated to metal and free radical imbalance and toxicity, which took placeat Limassol, Cyprus, October 25–31, 2006 (1). Major emphasis was givento iron chelation therapy in thalassemia and other conditions of transfu-sional iron overload, and in particular, the design and monitoring ofimproved therapeutic protocols, and also of ethical aspects related to thedevelopment and applications of new chelating drugs in developed anddeveloping countries.

Iron overload affects thousands of transfused patients with many con-ditions such as thalassemia, sickle cell anemia, myelodysplasia and hemo-dialysis, and also other categories of patients with increasedgastrointenstinal iron absorption such as in idiopathic hemochromatosis(2,3). The condition with the highest morbitidy and mortality rateaffected by transfusional iron overload toxicity and of chelating drugrequirements is thalassemia, which has an estimated annual birth rate of100,000 and is mainly distributed in the developing countries of SoutheastAsia, Middle East and the Mediterranean (Table 1) (3). However, despiterecent advances most thalassemia patients do not receive adequate treat-ment because of the lack of facilities and prohibitive costs, mainly in rela-tion to chelation therapy (2–4).

Transfusional iron overload toxicity affects the heart resulting inarrhythmias and congestive cardiac failure, which is the major cause of death

TABLE 1 Epidemiological Data on Thalassemia and Other Transfusional Iron Loaded Conditions

Most common chronic conditions treated with red blood cell transfusions

Thalassemias, sickle cell anemia, myelodysplasia/myelofibrosis, aplastic anemia, hemodialysis, cancer

Approximate number of red blood cell transfusions 2–3 units every 2–4 weeksDistribution of thalassemia Southeast Asia, Middle East, MediterraneanEstimated annual birth rate of babies with thalassemia About 100,000Survival of thalassemia patients without red blood cell

transfusions1–4 years

Survival of transfused thalassemia patients without chelation therapy

16–20 years

Mean survival of transfused thalassemia patients treated with DFO

35 years (some compliant, well-chelated patients exceeded 50 years)

Mean survival of transfused thalassemia patients treated with L1 or L1/DFOa

>35 years

aNo sufficient data are yet available for precise estimation but substantial improvements in reducing congestive cardiac failure deaths have been observed at many centers worldwide.

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Ethical, Cost, Safety and Efficacy Issues of Chelators 3

in thalassemia and other groups of transfused patients. The liver, pancreasand endocrine glands are also affected by excess iron, and this may result inliver fibrosis, diabetes, diminished growth and absent puberty (2,4).

Transfusional iron overload can be treated using chelating drugs, whichshould be effective at increasing iron excretion, in maintaining negativeiron balance (iron excretion > iron absorption + iron from transfusions)and low, safe iron levels in organs, most importantly, the heart. The almostdaily administration requirements of chelating drugs envisage that theseshould have low toxicity and good compliance. All these parameters areusually considered for the design of effective and non toxic iron chelationprotocols. Additional considerations are the cost of the chelating drug orchelating drug combinations, especially in developing countries where suchtreatments are considered very expensive.

The iron chelating drugs, which are widely used in transfusional ironoverload are deferoxamine (DFO), deferiprone (L1) and deferasirox(DFRA) (Figure 1). Many other chelators are under pre-clinical evalua-tion and some, such as deferitrin, are under clinical development, aimingfor an expanding market with annual sales currently estimated at 0.5billion euros.

The most widely used chelating drug is DFO, which was introduced inthe 1960s. Despite that DFO can achieve negative iron balance, mostpatients cannot use it effectively mainly because of low compliance with itssubcutaneous (sc) or intravenous (iv) administration, high cost and toxic-ity (4,5). The orally active chelator L1, which was mostly developed byacademic initiatives, was approved in India in 1995 and the EuropeanUnion (EU) in 1999, but has not yet been approved by the Food andDrugs Administration (FDA) in the USA (6). Deferasirox is the latestdeveloped orally active chelator, which was conditionally approved by theFDA in 2005 and also the EU in 2006 under the speedy orphan drug pro-cedures (7). Thousands of transfusional iron loaded patients includingthalassemia, myelodysplasia and sickle cell disease patients are currentlyusing DFRA. Many recent studies and reviews have been published sug-gesting that DFRA is relatively effective, well-tolerated and a safe drug,raising the hopes of many patients for a better treatment, especially thosewho cannot tolerate or afford DFO and L1 (8–12). However, post market-ing reports on DFRA, which were released in October and November2006 in the USA, have disclosed fatalities, which were caused by acuterenal failure, and also new serious toxic side effects such as agranulocyto-sis and other cytopenias (13,14). Furthermore, the price of DFRA is manytimes higher than that of DFO and L1, thus limiting its universal role. Theefficacy of DFRA is also in doubt, since there is no evidence that it canachieve negative iron balance or clear excess cardiac iron (Table 2)(10,15).

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New and encouraging developments are also in progress in relation toeffective chelation therapy protocols using L1 and in particular, of the useof L1/DFO combination therapy, which appears to be almost universallyeffective in the rapid and efficient clearing of excess iron from the heartand other organs in thalassemia patients (16–21). The introduction of theICOC combination protocol of L1/DFO and other similar protocols,appear to have improved the survival rate of thalassemia patients (16,22).

Many questions have been raised, not only for the future use of DFRAand for chelation therapy strategies in general, but also on the risk and benefitassessment policies of regulatory authorities. Similarly, the responsibilities

FIGURE 1 The chemical structure of (a) DFRA, (b) DFO and (c) (L1).

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and marketing methods and drug pricing of pharmaceutical companies inrelation to orphan drugs which include iron chelating drugs, have alsobeen questioned.

PROPERTIES, RESULTS OF CLINICAL TRIALS AND TOXIC SIDE

EFFECTS OF DEFERASIROX

Deferasirox is a bis-hydroxyphenyl-triazole benzoic acid derivative (4-(3,5-Bis (2-hydroxyphenyl)-1H-1, 2, 4-triazol-1-yl)-benzoic acid), which has beendeveloped following pre-clinical testing of more than 700 compounds by theNovartis pharmaceutical company (Figure 1) (8,9). It is a lipophilic, chargedtridentate iron chelator, forming a 2 chelator:1 iron, charged iron complex atphysiological pH. It can also form complexes with trace metals such as copperand zinc, and cause variable decrease of their concentration in the serum ofiron loaded patients (8,13). The de-compartmentalization of these twoessential metals may also affect their concentration in the tissues, which maybe associated with toxicities related to the regulation of copper- and

TABLE 2 Properties and Effects of the Iron Chelating Drugs Deferiprone (L1), Deferasirox (DFRA)and Deferoxamine (DFO)

Molecular weight L1: 139; DFRA: 373; DFO: 561Molecular weight of the iron complex Fe (L1)3: 470; Fe (DFRA)2: 798; Fe DFO: 614Number of iron binding ligands at the

binding siteL1: 2 (bidentate); DFRA: 3 (tridentate); DFO: 6

(hexandentate)Partition coefficient (n-octanol/water) Kpar L1: 0.2; DFRA: 6.3; DFO: 0.02Elimination half-life L1: 47–134 min.; DFRA: 19 ± 6.5 hours;

DFO: 5–10 min.Therapeutic daily doses L1: 75–110 mg/kg; DFRA: 20–40 mg/kg;

DFO: 30–60 mg/kg (3–5 days/week)Daily doses for achieving a negative iron

balanceL1: >85 mg/kg; DFRA: >40 mg/kg;

DFO: 40–50 mg/kg (5 days/week)Iron excretion L1: urine; DFRA: feces; DFO: mainly urine but also

fecesTarget organ in iron removal L1: heart, liver; DFRA: liver; DFO: liver and heartMajor toxic side effects L1: agranulocytosis, neutropenia, joint/

musculoskeletal pains, gastric intolerance, nausea, zinc deficiency

DFRA: renal failure, skin rash, agranulocytosis, neutropenia, gastric intolerance, nausea, zinc and copper deficiency, hepatic toxicity, auditory and ocular toxicity; DFO: auditory and ocular toxicity, yersiniasis, mucormycosis

Clinical experience following approval L1: 12 year; DFRA: 1 year; DFO: 40 yearsSale price in Europea L1: 5.5 euros/g; DFRA: 60 euros/g;

DFO: 8.3 euros/g

aThe estimation does not include elastomeric or electronic pumps, syringes, needles, etc. for the DFO injections; regular monitoring for agranulocytosis, renal and other organ damage, etc. for L1 and DFRA; the total cost per day is also different, given that different therapeutic doses are used for each drug.

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zinc-containing enzymes and other biomolecules and biological processesdependent on these metals (2). The displacement of copper was previouslysuggested as a possible cause of agranulocytosis in patients treated with L1,which has now also been observed with DFRA (2,4,13,14).

Deferasirox appears to have high affinity and to form lipophilic com-plexes with aluminum. Chronic use of DFRA may increase the gastrointesti-nal absorption and accumulation of aluminum in the brain, which mayresult in the classical symptoms of aluminum overload, including symptomssimilar to those of Alzheimer’s disease patients (23). It was recommendedby the manufactures of DFRA that aluminum-based anti-acids should not betaken during treatment with DFRA (13).

It is also possible that DFRA can cause an increase in iron absorptionand de-compartmentalization of chelated iron in various organs, especiallythe kidneys resulting in renal damage. This mechanism of action may partlybe related to the increased renal toxicity and may be the cause of the fatali-ties in the reported irreversible renal failure cases (13,14). Similar effects ofincreased iron absorption and accumulation of excess iron in the liver andother organs in rats was previously observed with the lipophilic chelator8-hydroxyquinoline and with other lipophilic chelators such as maltol and1-hydroxy-4-methoxypyrid-2-one in mice (24,25).

Although thousands of patients have been receiving DFRA, only a smallnumber of clinical trials involving a small number of iron-loaded patientshave so far been published. In a summary report by the manufacturers ofDFRA, the clinical trials covered a period of about 4 years, some lasting upto 48 weeks and involving about 700 transfused patients, of whom 45% weremale and 292 were aged between 2 and 16 years. Most of the patients hadβ-thalassemia (thal) (469) but also included were patients with sickle cellanemia (132; 89% Black), myelodysplastic syndromes and other conditions.In addition, extended studies of median duration treatment of 85–143 weeks,have also been carried out involving 403 β-thal and 66 other patients (13).

In pharmacokinetic and metabolic studies, DFRA has been shown to beorally absorbed with a half-life of 1.5–4 hours, from the time of administra-tion to peak plasma concentration levels. In blood, DFRA is found almostexclusively bound to albumin (99%), mainly because of its lipophilic prop-erties. Deferasirox is mainly metabolized to a glucuronide conjugate, simi-lar to L1, but is also partly (8%) oxidized by cytochrome P450. Deferasirox,its iron complex and its metabolites, are mostly excreted in the bile andabout 8% in the urine. The elimination half-life of DFRA is about 19 ± 6.5hours at 20 and 40 mg/kg and is longer for its iron complex (10,11). Theslow rate of plasma clearance limits the prospects of repeated administra-tions of DFRA within the same day because of increased possibility of drugand byproduct accumulation toxicity. Consequently, the overall rate of ironremoval is limited and depends on a single daily dose.

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In iron metabolic balance studies, DFRA has been shown to be effectiveat increasing fecal, but not urinary iron excretion, and also in reducing liveriron and serum ferritin levels in some of the patients using the prescribeddoses of 10–30 mg/kg/day. In iron loaded thalassemia patients, doses of10–40 mg/kg have been shown to cause a net increase in iron excretion,which was dose-dependent but not sufficient to cause negative iron balance(>15–20 mg iron excretion) in the majority of patients at 20 mg/kg or evenin most cases at 30 mg/kg/day. Deferasirox is reported to be more effectivein most patients at 40 mg/kg with the mean iron excretion estimated at28 mg/day per 50 kg man body weight (10).

Despite the liver iron removal findings by DFRA, cardiac iron removalhas not yet been convincingly shown in patients participating in the clinicaltrials in the last 5 years or in post-marketing reports. However, cardiac ironremoval has been shown in animals using magnetic resonance imaging(MRI) T2* relaxation time measurements at much higher doses (100 mg/kg/day) than those prescribed for patients (20–30 mg/kg/day) (26). Incontrast to DFRA, cardiac iron removal using MRI T2* has been shown byL1, iv DFO and the L1/sc DFO combination in thalassemia patients withina year of treatment (16–21).

Many toxic side effects, including fatalities, have been reported duringthe post marketing surveillance period of DFRA. The fatal cases reportedwere related to acute, irreversible renal failure in transfusional iron loadedpatients (13,14). Renal toxicity appears to affect about one-third of thepatients treated with deferasirox and until recently this toxicity was thoughtto be controllable and reversible (27,28).

In addition to the fatalities, new toxic side effects of cytopenias includ-ing agranulocytosis, neutropenia, and thrombocytopenia caused by DFRAhave also been reported (13). It is worth noting that no such life-threaten-ing toxicities have previously been reported, or anticipated, from animaltesting or in the pre-registration clinical trial period with DFRA.

In previous clinical studies, several other toxic side effects have beenreported for DFRA including auditory and ocular abnormalities, gastrointes-tinal symptoms (nausea, vomiting, diarrhea and abdominal pain), headache,cough, skin rash, hepatitis, transaminitis and increase in serum creatinine(8–14,28). In contrast to the other serious toxic side effects, gastrointestinalsymptoms, increase in serum creatinine and skin rash appear to be doserelated. A total of 23 adverse events were recorded to affect >5% of β-thalpatients in one study. About another 13 uncommon adverse reactions affect-ing 0.1–1.0% of the 700 patients were also recorded (13). In one study involv-ing sickle cell anemia patients the withdrawal rate due to adverse events was11% (12). The most common adverse events leading to drug withdrawal wereskin rash, gastrointestinal disorders, increased serum creatinine, increasedserum transaminases, infections, hepatitis, thrombocytopenia, neutropenia

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and agranulocytosis (13). The cause of the reported toxic side effects as wellas whether these are related to the DFRA molecule, its metabolites or metalcomplexes, is still unknown. However, a number of prophylactic measures,which could be used to minimize fatalities and other serious toxic sideeffects of DFRA have been suggested (13,28). For example, restrictions ofits use could be applied to patients with pre-existing renal conditions orhematological conditions related to bone marrow failure and also topatients receiving pharmaceutical preparations that are known to causerenal function depression, agranulocytosis, neutropenia, and thrombocy-topenia. Regular serum creatinine (initially weekly and then monthly) andurine proteinuria levels as well as weekly white blood cell count (WBC)monitoring is recommended for all patients using DFRA (28). Interruptionof the treatment has been recommended in the seriously affected patients,until the causes of the toxicities have been elucidated (13,28). Continuousand thorough monitoring is required for such serious toxicities, since fatali-ties from agranulocytosis and other cytopenias have already occurred withpatients treated with L1, DFO, the L1/DFO combination and DFRA (4,28–31)The withdrawal of DFRA is also recommended for patients affected byother toxic side effects including those with increased serum transaminases,infections, hepatitis, ocular and auditory abnormalities, etc. (13,28).

No reports of drug interactions have yet been reported or studied.Selected combination therapy protocols of DFRA with L1 and DFO areexpected to improve iron removal efficacy and minimize DFRA’s toxicity(30). In relation to metal interactions by DFRA, and the suspectedincreased absorption and de-compartmentalization of metal ions such asiron, aluminum, zinc and copper, similar effects could also be expected fortrace amounts of toxic metals present in food such as nickel, cobalt, lead,arsenic and mercury.

The monitoring of serum ferritin levels and withdrawal of DFRA wasalso recommended in patients with serum ferritin levels below 0.5 mg/L inorder to minimize the prospects of toxicity of excess non iron bound drug.The general effects of DFRA in patients with high serum ferritin levels(>5 mg/L), increased cardiac iron stores and geriatric patients are still notknown.

RISK AND BENEFIT ASSESSMENT IN THE USE OF DEFERIPRONE,

DEFEROXAMINE AND DEFERASIROX: IMPLICATIONS ON

GENERAL CHELATION STRATEGIES

The response of thalassemia and other iron loaded patients to any formof iron chelation therapy is variable with regards to efficacy and toxicity. Ineach case, a risk and benefit assessment is considered for the selectedchelating drug(s) and protocol. The advantages and disadvantages of the

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use of L1, DFO and DFRA have been previously reviewed (2). In somepatients, optimum therapy can be achieved by L1, DFRA or DFO monother-apy, but for the vast majority of transfused patients the use of effective L1/DFOcombination protocols, such as the ICOC protocol, appears to provide com-plete, rapid and effective solutions in the treatment of iron overload (16).Similarly, the use of other possible combination protocols involving DFRAmay also benefit some patients, especially those having toxicity or compli-ance problems with L1, DFO and their combination (32).

There are many limitations associated with the selection and use ofchelating drugs, especially with regards to efficacy, toxicity and cost (Table 2).Switching from one to another chelating drug may be considered forpatients who are sensitive or not responding to a particular drug or drugcombination. Similarly, targeting iron removal from a particular organ mayalso be important, and the selection of a chelating drug or drug combina-tion may be used for improving overall chelation therapy or specific organfunction (2).

Within this context, DFRA does not appear to be a suitable alternative toL1, intensive iv DFO or the L1/sc DFO combination for the clearance ofexcess cardiac iron and the prevention or reversal of transfusional iron over-load cardiomyopathies. Similarly, DFRA may be more appropriate for somepatients for the clearance of excess liver iron by comparison to L1 or DFO (2).

The mechanism of action, including the differences in the pharmaco-logical and toxicological effects and of the efficacy in iron removal from thedifferent organs between L1, DFRA and DFO, is based on the physicochem-ical, metabolic and clearance characteristics of the individual drugs, theirmetal complexes and their metabolites (2). With regards to toxicity, most ofthe toxic side effects reported for DFRA are not typical of either L1 or DFO,but the report of fatalities from renal failure during treatment with DFRA isa major setback for its worldwide use and problematic for its future applica-tions not only as a monotherapy but also in combination therapies.

In the light of the fatalities and of the new serious cytopenia toxicities,the risks for using DFRA have substantially increased and the number ofpatients that can benefit reduced. Pending further information on theextent of these toxicities with DFRA, the risks appear to outweigh the bene-fits for most groups of patients, especially since the existing therapies withL1 and DFO offer much lower toxicity rates and much higher efficacy.

Further updated evaluation on both the long-term efficacy and toxicityof DFRA will be provided following the ongoing long-term use of DFRA andthe post marketing surveillance investigations, which have been requestedby the regulatory authorities (7,27). The identification of the mechanismscausing the toxic side effects and the possible prophylactic measures thatcan prevent them could result in a substantial improvement in the thera-peutic profile of DFRA, L1 and also DFO.

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ETHICAL CONSIDERATIONS BASED ON THE COST

OF CHELATION THERAPY AND ITS INFLUENCE ON

CHELATION STRATEGIES AND LONG-TERM SURVIVAL

OF THALASSEMIA PATIENTS

Whatever the outcome of further developments with DFRA, it isunlikely that there would be any benefits from its use for the vast majority ofpatients requiring chelation therapy, especially thalassemia patients livingin developing countries, due to the prohibitive price of the drug. It is esti-mated that the cost of DFRA in countries under patent control is about60 euros/g compared to 5.5 euros/g for L1 and 8.3 euros/g for DFO. Thisestimate does not include expenses for the injection costs of DFO or thehigher doses of L1 that are needed, as well as the expenditure for monitor-ing toxic side effects. The cost of DFRA is excessive not only for developingbut also for developed countries, and this may not encourage its use bypatients, especially those not responding or having problems with theadministration of L1 and DFO.

In the meantime, it appears that in countries where there is no patentprotection for DFRA, either because patents were not filed on time orpatent control is not yet mandatory, e.g., India and Iran, the drug could bemanufactured and provided to local thalassemia and other transfusedpatients at much lower prices. Similar developments have occurred with L1in India, where a local pharmaceutical company is selling L1 at 3–5 timescheaper than the price in Europe. It is hoped that the price of L1 will fur-ther be reduced when the patent in Europe expires in 2008, despite that, inthe case of DFO, the price remained the same following expiration of therelated patent several years ago. In the case of L1, however, the prospect ofprice reduction is more realistic because the method of synthesis is very sim-ple and the starting materials inexpensive, thus allowing more pharmaceu-tical companies to be involved in the manufacturing and marketing of thedrug even at a local level (32,33).

In addition to the cost and risk/benefit assessment of chelator, or chela-tor combinations, several other factors are influencing chelation therapystrategies worldwide including marketing monopolies and policies. Thesemay also influence academic and health institutions and individuals,patients’ organizations, etc. The development and marketing of iron chelat-ing drugs also highlights the great gap on orphan drug policies, and theavailability prospects of new drugs for patients in developed and developingcountries, where the former are the proprietors and the latter the prospec-tive buyers with a great disadvantage in buying power.

Long-term survival and good life quality are considered as the most sig-nificant parameters influencing overall chelation strategies for individualpatients. In each case, a risk and benefit assessment would be required

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either for the use of a chelation monotherapy or combination therapy.Within this context, cardiomyopathy caused from excess cardiac iron depo-sition is considered as one of the main targets of chelation therapy(5,17,18). Although L1 (80–100 mg/kg/day) and the L1/DFO combination,are effective in preventing this damage, there is no evidence that DFRA canhave the same effect at the prescribed doses (20–30 mg/day) (16,26).

There is increasing evidence of long-term survival of thalassemiapatients worldwide since the introduction of L1 (19,22). This is partlybecause of the wider availability of L1 due to the affordable lower cost che-lation therapy in developing countries and also due to an increased compli-ance by comparison to sc DFO. Similarly, the introduction of effective L1/DFOcombinations has provided, in many cases, more effective and less toxicchelation treatments than previous monotherapies. A major factor in theincreased survival of thalassemia patients using L1 is related to the muchhigher ability of L1 to prevent iron accumulation in the heart and to removeexcess cardiac iron by comparison to other chelating drugs (2,16,18).

THE ROLE OF REGULATORY AUTHORITIES AND

PHARMACEUTICAL COMPANIES ON THE DEVELOPMENT

OF ORPHAN IRON CHELATING DRUGS

The DFRA’s post marketing reports on the fatalities and other seriouscytopenia toxicities were disclosed only a few months after the conditionalapproval of the drug by the EU regulatory authorities in 2006 and the FDAin 2005 (13,14). Thousands of patients and clinicians using, or planning touse DFRA, are still not aware of the existence of the post marketing toxicityreports (13,28). Similarly, there is not yet any information on the possiblecauses, post mortem findings or the prophylactic measures that are neededto prevent renal failure fatalities and the other life-threatening toxicities.Also not known are the numbers, incidence rate, age, sex, categories oftransfused patients and the timing after initiating treatment, in relation tothe fatalities and the cytopenia toxicities.

Renal damage was one of the major forms of toxicity of DFRA, whichwas identified during animal studies (8). However, no information is avail-able regarding any investigations that were proposed or carried out to iden-tify the mechanism of renal toxicity. Accumulation of the drug, itsmetabolites and iron complexes in the kidneys may partly be the cause ofthe toxicity. There are many other possible mechanisms that may causetoxic side effects by lipophilic chelators, which are not typical of otherdrugs. In general, the toxicological procedures usually adopted for otherdrugs cannot identify the cause of the toxicity by chelators, because of thepresence of multi-molecular species involving metal complexes of the chela-tor and its chelating metabolites. Specialized screening procedures such as

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MRI, or other techniques for examining iron accumulation in the kidneys,would be required to identify possible causes for the renal failure in thecase of lipophilic chelators such as DFRA. Similar efforts should also bemade to identify the causes and for the prevention of agranulocytosis inpatients treated with DFRA and L1 (28–31).

The toxicity findings on DFRA, question, among other things, theapproval procedures adopted by the EU regulatory authorities, and theFDA in particular. This applies not only on DFRA, but also on L1 and otherorphan drugs.

In the case of L1, the approval by the FDA in the USA is still pending,despite the fact that it has been approved and used in India since 1995 andin the EU since 1999. As a result, thousands of thalassemia and other ironloaded patients receiving regular transfusions in the USA and countriesinfluenced by the FDA, have not yet benefitted from the use of L1 or itscombination with DFO. This delay is affecting mainly patients with ironoverload toxicity related cardiomyopathy, which is the main cause of deathin transfusional iron overload.

The events surrounding the development of L1 and DFRA, and theapproval procedures adopted in each case, are completely differentbetween the EU regulatory authorities and the FDA. These differenceshighlight the imbalance in the risk and benefit assessment of regulatoryauthorities such as in this case the FDA, where stringent or relaxed regula-tory conditions may not benefit patients in the long-term. The policy deci-sion against the use of L1 by the FDA, and that of other regulatoryauthorities, may have caused an increase in the cardiomyopathy and mortal-ity rate of thalassemia patients in the USA and other territories.

The design and development of L1 is a prime example of the role ofacademic research in the design and development of orphan drugs for thebenefit of patients worldwide. In this case, adverse events were openlyreported and published as soon as identified. The example of L1 is ques-tioning the established system of drug development by most pharmaceuti-cal companies, which is driven by almost exclusive marketing monopoliesdue to patent ownership and excess profit, and where information, espe-cially on adverse effects, is not readily available or easily and fully disclosed.

The responsibility for early and detailed disclosures of serious adverseeffects should not only involve the pharmaceutical companies and the clini-cians in charge but also the regulatory authorities. Such information shouldhave reached all patients and clinicians using, or planning to use, any new drug.

The high cost of DFRA raises further questions on the proceduresadopted for the pricing of drugs, and in this case, of orphan drugs. Pricefixing, exclusive monopolies and heavy marketing policies pursued by somepharmaceutical companies for new drugs usually put patients in the devel-oping countries at a disadvantage. The procedure on price fixing is not yet

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fully clarified and transparency on the methods for the marketing prices ofdrugs is required. For example, DFO became a generic drug many years agobut its price was not reduced. Despite that, the price of L1 in India is 3–5times cheaper than in Europe; further price reduction after the expirationof the patent in 2008 is expected, which may benefit more patients in thedeveloping countries who are not currently receiving any form of chelationtherapy because of its high cost. It should be noted that the sale price ofDFRA is more than 100-times more expensive that the cost of its synthesis.The same applies to L1 but to a lesser degree (10–20 times).

It would appear that the current established marketing monopoly meth-ods of pharmaceutical companies are of little benefit to the vast majority ofthalassemia and other transfused patients, most of whom live in the devel-oping countries. The situation is very similar to the fate of AIDS patients inthe developing countries, where access to expensive antiviral drugs is verylimited. There is a need for reassessment of drug policies and drug pricesfor benefitting patients both in developed and developing countries.

CONCLUSIONS

Reassessment of the risks and benefits and prophylactic measures forthe use of DFRA are urgently needed for preventing more fatalities inthalassemia and other transfused patients. The high costs of chelating drugsdeprive many thalassemia patients in developing countries of essential ther-apy, which is required for their survival. New rules and regulations areneeded for the operation, drug policies and decision making by regulatoryauthorities on orphan drugs. The pricing policy and reporting methods ofadverse effects by pharmaceutical companies needs to be reviewed. Priorityshould be given to the safeguarding of patients from fatal toxicities, andalso for pricing procedures that could benefit patients not only in the devel-oped but also the developing countries. The safety and efficacy record ofL1, DFO, and their combination in particular, at present appears to provideuniversal and safe solutions for the treatment of transfusional iron overloadin thalassemia and other conditions.

Please note that fatal liver failure cases have been reported by the FDAin 2007 for patients using DFRA.

ACKNOWLEDGMENTS

I would like to thank the authors and reviewers of the 16th ICOC pro-ceedings; the members of the ICOC committee, the organizing and scien-tific committees, the participants, the sponsors and exhibitors of the 16thICOC conference and all others who contributed to the successful organiza-tion of the conference and the production of the 16th ICOC proceedings.

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ethical issues and risk/benefit assessment of iron chelation therapy: advances with...

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