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Access to anti-cancer drugs: Many evidence-based treatments are off-label and

unfunded by the PBS1

James D Mellor MPharm (Hons), SpecCertCR(Onc), MRPharmS1,2

Pia Van Koeverden1,2

Sing Wang Kevin Yip2

Arti Thakerar BPharm1

Suzanne W Kirsa BPharm, Grad Dip Hosp Pharm FSHP1

Michael Michael MBBS (Hons), BSc (Hons), MD, FRACP3

1. Pharmacy Department, Peter MacCallum Cancer Centre, St Andrew’s Place, East

Melbourne, Victoria, Australia

2. Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria,

Australia

3. Division of Cancer Medicine, Peter MacCallum Cancer Centre, St Andrew’s Place, East

Melbourne, Victoria, Australia

Correspondence to:

Dan Mellor, Deputy Director of Pharmacy, Pharmacy Department, Peter MacCallum Cancer

Centre, St Andrew’s Place, East Melbourne, VIC 3002, Australia.

Tel: +61 3 9656 1213 Fax: +61 3 9656 1405 Email: dan.mellor@petermac.org

Key Words: Oncology; Haematology; Off-label; Unlicensed; Chemotherapy; Reimbursement;

PBS

Word Count:

This is an Accepted Article that has been peer-reviewed and approved for publication in the Internal Medicine Journal, but has yet to undergo copyediting and proof correction. Please cite this article as an “Accepted Article”; doi: 10.1111/j.1445-5994.2012.02751.x

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Abstract: 250

Main Text: 2902

ABSTRACT

Background

The off-label use of a drug refers to a use outside the terms of its approval by the Therapeutic

Goods Administration’s (TGA). It is also possible to prescribe unlicensed drugs under the

Therapeutic Goods Administration’s (TGA) Special Access Scheme. A high rate of off-label

prescribing has previously been reported in cancer. Our study aimed to document the disparity

between clincial evidence-based guidelines for anti-cancer therapy, product approval, and

funding status of these agents within an academic tertiary/quaternary cancer centre.

Method

All chemotherapy protocols approved for use in our specialist oncology centre were assessed to

determine if the drugs were off-label or unlicensed for that indication based upon review of their

current product information. The Pharmaceutical Benefits Scheme (PBS) funding status for

each protocol was subsequently assessed.

Results

A total of 448 protocols, containing 82 different drugs, across 15 tumour groups were identified.

Overall, 189 (42.2%) of protocols were off-label and 3 (0.7%) were unlicensed. This resulted in

all 192 protocols being unfunded by the PBS. Of the 189 off-label protocols, 132 (69.9%) were

based on established evidence-based treatment guidelines and a further 39 (20.6%) were

based upon phase II or III clinical trial data.

Discussion

Over 90% of off-label protocols are supported by established treatment guidelines or published

peer-reviewed research even though the medications are not approved for that particular use by

the TGA. However, these off-label protocols are unfunded by the PBS: this results in a marked

inequality of access to appropriate medications for cancer patients across Australia.

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INTRODUCTION

There is a high prevalence of off-label prescribing in the cancer setting, where substantial

differences exist between indications approved by regulatory authorities and the standards in

clinical practice 1-3. Off-label prescribing refers to the use of a drug, which has been approved

by the Therapeutic Goods Administration (TGA), for indications that fall outside the terms of the

official ‘labelling’ or product approval. The TGA assesses the safety and efficacy of drugs for

each specific use, a process entirely separate to an application for government reimbursement

of a drug. A prescription may be off-label for a number of different reasons, including:

indication, dose, combination of medications, schedule and route of administration, as well as

duration and line of treatment4. Many physicians prescribe in this manner, generally based on a

high level of evidence, when there are no suitable alternatives and it may be the only treatment

option for cancer patients5.

The use of unlicensed anti-cancer drugs (drugs which have not been approved for any

indication) is less common. In Australia this is made possible under the TGA’s Special Access

Scheme (SAS). A drug may be unlicensed because it has never been submitted for evaluation,

it has been evaluated and rejected by the TGA, or the sponsor has withdrawn the drug from the

market (forced or voluntarily). The lack of regulatory approval for a specific indication does not

imply that the TGA disapproves of an off label use, but rather, indicates that they have not

reviewed the use of that particular medication in the clinical setting concerned. This often arises

as the relevant pharmaceutical company has not submitted the agent for that specific indication

(for logistical or market issues) or the agent is off-patent. The companies have no legislative

requirement or obligation to submit for an indication.

It is important to note that off-label and/or unlicensed prescribing is not necessarily unsupported

by clinical data, of variable quality, and often does form part of standard treatment

guidelines.2,3,6-8 Furthermore, these drugs may have been approved in another jurisdiction, e.g.

the Food and Drug Administration (FDA) in the USA.

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Patients need access to beneficial off-label treatments that are based on scientific evidence but

at the same time, they require protection from off-label interventions that are risky and

ineffective5. Whilst it is preferable that all uses of drugs and devices are supported by research,

this is not always available or feasible. Thus, it is the responsibility of the prescriber to ensure

that any off-label use of a drug or device is truly appropriate5.

An Australian study, which examined the prevalence of off-label or unlicensed prescribing at a

specialist cancer hospital, found that between 2001 and 2008, prevalence increased from 22%

to 39% (expressed as a percentage of total prescriptions) and in 2008, 85% of patients were

prescribed at least one drug which was unlicensed or off-label1. This study included all drugs;

anti-cancer drugs, supportive care drugs and drugs not directly related to cancer. An American

study which analysed the records of 185,000 cancer patients between 2003 and 2008 reported

that 68% of breast cancer patients and 95% of lung and bladder cancer patients were

prescribed drugs which were not FDA approved for these cancers. However, the majority of

patients (99.7%) received treatment within the National Comprehensive Cancer Network

(NCCN) guidelines, illustrating the level of disparity between standard treatment guidelines and

regulatory-approved indications8. These prescribing patterns were also supported by an Italian

study3.

In addition to the therapeutic issues associated with the off-label drugs, there are also cost

factors that need to be discussed with patients7. The Pharmaceutical Benefits Scheme (PBS)

list certain drugs, recommended by the Pharmaceutical Benefits Advisory Committee (PBAC),

for reimbursement based upon cost-effectiveness. The listing of a drug may be unrestricted

(but limited to TGA approved indications) or may be restricted to certain indications, which may

be narrower than the TGA approval. It is important to note that a drug cannot be listed or

reimbursed under the PBS for an unapproved (off-label) indication, i.e. they require licensing for

that indication by the TGA.

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Our study aimed to determine the proportion of chemotherapy protocols used in a specialist

cancer hospital that include off-label and unlicensed prescribing. Furthermore, we aimed to

identify which of these drugs are part of established treatment guidelines even though they are

not be approved by the TGA and therefore unfunded by the PBS.

METHOD

A complete list of chemotherapy protocols used at the Peter MacCallum Cancer Centre was

obtained from CHARM®, an cancer medicines management software program. Protocols were

added to the program from November 2008 onwards. Protocols were incorporated by the

relevant haematology and medical oncology subspecialty group based on the highest level of

evidence for each indication derived from national and international guidelines, meta-analyses,

phase III trials etc and are reviewed on an annual basis.

Each protocol was analysed and the drugs forming each protocol were compared against their

approved indications (and approved combination of drugs, where applicable) according to the

current Australian product information for all brands of the drug (sourced from MIMS and the

TGA website) in addition to the PBS criteria for their reimbursement status (from the PBS

website). This comparison was performed during December 2010. Clinical trial protocols and

protocols for supportive therapy (e.g. iron infusions for the treatment of anaemia) were

excluded. All other protocols were included in the analysis.

Within each protocol, drugs were categorised as being licensed (approved by TGA for that

specific indication), off-label (TGA approved for other indications or disease settings) or

unlicensed (not TGA approved). The drugs were also categorised according to their PBS

reimbursement status as either funded (divided into restricted or unrestricted) or unfunded.

Indication (i.e. cancer type) and drug combinations were considered when categorising drugs

and protocols. When categorising drugs, the disease setting for which they were approved (or

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PBS funded) was taken into account: i.e. if only for adjuvant therapy or only for metastatic

disease. Factors such as dose, infusion rates, dosage form, and place in therapy (e.g. as first

line therapy or as treatment for refractory disease in the metastatic setting etc.) were not

considered.

For each protocol, if one or more drugs were off-label, then the protocol was considered off-

label (or unlicensed where applicable). The same principle was applied to PBS listing; if one or

more drugs in a particular protocol were not eligible for PBS funding, then the protocol was

considered to be unfunded.

Where a protocol was considered off-label or unlicensed, a search of established cancer

treatment guidelines was conducted to verify the level of clinical evidence for that particular

regimen. Guidelines consulted included those of the National Comprehensive Cancer Network

(NCCN), British Columbia Cancer Agency (BCCA), Cancer Care Ontario (CCO) and the New

South Wales Cancer Institute (eviQ database). Where protocols were not contained within any

established consensus guidelines, a primary literature search was conducted to determine the

highest level of available evidence for its use. Primary literature searching was conducted using

the Medline and EMBASE databases.

RESULTS

A total of 448 protocols, containing combinations of 82 different drugs, were included in the

analysis. 192 protocols (42.9%) contained at least one drug which was being used in an off-

label or unlicensed indication or was being used in an off-label combination. Therefore all 192

protocols are unfunded by the PBS. Of those 189 off-label protocols (i) 132 (69.9%) were

supported by evidence from one or more established cancer treatment guidelines, (ii) 39 off-

label protocols (20.6%) were based upon phase II or III clinical trials, (iii) 18 (9.5%) protocols

had no available published evidence to support their use for the indication in which they were

being used.

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INSERT FIGURE 1 HERE

Over 50% of off-label protocols were identified for the following malignancies: head and neck,

central nervous system (CNS), skin, gastro-intestinal, gynaecological, lung,

transplantation/mobilisation, sarcoma. The majority of these having protocols based upon

established treatment guidelines ranging from 60-90%.

Three protocols (0.7%) contained drugs which are unlicensed in Australia. The three protocols

containing unlicensed drugs were not found in any established guidelines, but were supported

by primary research reports.

INSERT TABLE 1 HERE

In the six months from 1st July 2010 to 31st December 2010, 234 of the 448 protocols had been

prescribed for at least one cycle of treatment. The remaining 214 protocols remained as

options within CHARM® but had not been used within the selected six month period.

DISCUSSION

Off-label prescribing is an integral part of patient care in cancer. The results of this study

demonstrate that whilst the incidence of off-label prescribing is high, the majority of off-label

chemotherapy prescribing is supported by established clinical guidelines or evidence from

primary research reports. A much smaller number of protocols were supported by lower levels

of evidence such as phase II trials. A significantly smaller number of protocols had no

published evidence available to support their use for their intended indication, however most of

these protocols (drug combinations, doses etc.) were available in guidelines or published

primary literature for other diseases. This suggests that in certain instances, off-label

prescribing may be based upon extrapolation of clinical data supporting the efficacy of a therapy

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in one cancer to other cancers with similar pathophysiology, for example, head and neck

squamous cell carcinoma (SCC) therapies are used in the treatment of SCC of the skin.

Off-label prescribing of drugs has been reported for most types of cancer, but may be more

common in certain types of malignancy. For example, other studies have reported a lower

incidence of off-label prescribing in breast cancer when compared with bladder cancer or

hormone refractory prostate cancer4. Furthermore, off-label use of drugs was higher in cases

where there was no consensus on the optimum therapy and patients with metastatic and

advanced forms of rare malignancies. Off-label use is also more likely to be seen for drugs with

a narrow range of indications but with a broad spectrum of activity4.

Due to the aggressive nature of some cancers, prescribers may be more likely to consider off-

label drug use, especially for patients where all other licensed treatment options may have been

exhausted. Our analysis found that tumour types such as breast and leukaemia had a lower

incidence of off-label drug use than some of the rarer tumours perhaps reflecting the greater

availability of licensed drugs in these settings.

Lack of regulatory approval for chemotherapy drugs may be, in part, due to difficulty in obtaining

the required level of evidence to support an application for approval. For rare cancers, it may be

difficult to obtain sufficient numbers of participants to generate high quality clinical trial data for

an approval submission. For treatments for such tumours, the TGA approval may seem an

unrealistic goal, unless it was obtained via the orphan drugs pathway. Orphan drugs are defined

by the TGA as a drug that is intended to treat, prevent or diagnose a rare disease; or is not

commercially viable to supply to treat, prevent or diagnose another disease or condition. On the

other hand, even where high level clincial data exists for a rare cancer, pharmaceutical

companies may be reluctant to submit for licensing for marketing reasons or where the drug has

come off patent. Pharmaceutical companies are not mandated to submit to any regulatory

process, but on the other hand, they are the only organisations that have the resources to

enable a submission.

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This study demonstrated that a large proportion of protocols which were not TGA approved,

were included in evidence-based clinical guidelines (in many cases, from multiple institutions).

This indicates that there is a substantial, thus unacceptable, delay between incorporation of

clinical evidence into standard practice and/or guidelines and regulatory approval. Cancer is a

very research-intensive area of medicine and as such, the best available evidence is rapidly

changing, along with trends in standard treatments. Lengthy government approval processes

which drugs must be subjected to may be inappropriate in a cancer setting and result in failure

to incorporate the most recently available evidence in a timely fashion. This may be

problematic for prescribers who utilise the official product information to guide their prescribing

decisions as TGA approved product information often does not contain the most current or best

available evidence.

Following initial TGA approval of a drug, the TGA will only incorporate additional indications if

the company resubmits the drug for approval for use in these additional indications. This

process is costly and time consuming for pharmaceutical companies and is often not

undertaken. This is particularly so if there is perceived to be little financial incentive, but as well

the companies are under no legal obligation to submit new indications or change the Product

Information. This may be the case for older drugs which are not TGA approved for certain

indications, but have been incorporated into standard treatment guidelines for these indications

over long periods of time and are generally accepted as part of standard care. This is

particularly relevant where generic versions are available. This has resulted in older (cheaper)

chemotherapy drugs thus being used off-label and therefore unfunded by the PBS whilst many

expensive novel therapies are licensed and reimbursed.

Lack of TGA approval of drugs can also cause issues when attempting to conduct multinational

clinical trials in Australia. In head to head trials, the standard of care arm (comparator) may

contain drugs or protocols that are widely used overseas but not licensed by the TGA for the

specific indication being evaluated in the trial. There is a risk that in these situations local ethics

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committees may not allow the trial to proceed due to the lack of TGA approval of the standard

treatment arm.

PBS funding is related to a cost-benefit analysis and not necessarily directly related to TGA

approval (although drugs must be TGA approved before they may be considered for PBS

listing). Furthermore, drugs which are only administered in the in-patient setting are not PBS

funded in public hospitals, even if they are PBS listed for that indication. In our centre, non-PBS

funded drugs must be approved for use by the Pharmacy and Therapeutics Advisory Committee

(PTAC). This is a multidisciplinary committee that examines the clinical data and cost of

medicines. The funding in such cases therefore needs to come from either the treating

institution or the patient (from personal funds or occasionally private health insurance funds if

insured). Cancer patients ethically should not be denied access to active agents in the

treatment of their malignancy. On the otherhand, in the era of limited health resources, funding

bodies need to remain mindful of cost-effectiveness and issues of risk-benefit. This can result in

the best available treatments not being made available due to the limited nature of public funds.

There were 18 protocols that had no available published evidence to support their use for the

indication in which they were being used. It is possible these protocols were being used on the

basis of abstracts that were presented at conferences but were not published, or case reports,

or discussions with key international opinion leaders (based on their own experience). These

protocols tended to be used for rarer malignancies or in unusual circumstances of common

malignancies.

There was an agreement with the medical streams (haematology and medical oncology) about

which protocols could be entered into CHARM®. Those that contained drugs not approved by

the PTAC, were clearly labelled as “Individual Patient Approval (IPA) required” to indicate the

processes that must be followed before a patient could be put onto that particular protocol. An

IPA requires formal approval from the head of the relevant stream and notification in advance to

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the pharmacy department. All IPAs are tabulated and reported at the next PTAC meeting for

noting and discussion if necessary.

There are several limitations to this study. All protocols analysed in this project were sourced

from a cancer medicines management database at a single institution and it is possible, but

unlikely, that they may not reflect current clinical practice at other institutions. Protocols were

only evaluated according to the pathways or diseases by which they were categorised in the

computer database. This method does not account for prescribers who may use a protocol for

a different, uncategorised indication. Some protocols had ambiguous indication categorisation

(e.g. “Other GI”) which made determining whether the drugs used were being used in an off-

label setting difficult. A clinical judgement was made in this small number of cases to identify

the most likely indication of use. In addition, no assessment was made as to which protocols

could be administered in the out-patient or same-day patient setting as public hospitals cannot

claim drugs administered to inpatients from the PBS. This difference in funding arrangements

between inpatient and day/outpatients can act as a barrier to the appropriate use of drugs in

cancer patients.

Conclusion

Our study found that over 90% of off-label protocols used in cancer patients were supported by

established clinical guidelines and/or peer-reviewed research publications. Our study

demonstrates that despite the existence of such a high level of evidence, many cancer

treatments are not TGA approved. This results in a lack of PBS reimbursed treatment options

for cancer patients and may potentially impact on the success of their cancer therapy and thus

survival.

Moving forward it is imperative that professional groups work with key policy makers to develop

a framework for a rapid and logical oncology drug approval mechanism outside of the standard

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TGA process to prevent the process lagging behind the clinical evidence and remove a potential

barrier for patients accessing anti-cancer drugs.

REFERENCES

1. Mellor JD, Bensted KE, Chan PL. Off-label and unlicensed prescribing in a specialist

oncology centre in Australia. Asia-Pacific Journal of Clinical Oncology 2009;5(4):242-6.

2. Mullins CD, Montgomery R, Tunis S. Uncertainty in assessing value of oncology

treatments. Oncologist 2010;15 Suppl 1:58-64.

3. Roila F, Ballatori E, Labianca R, De Braud F, Borgonovo K, Martelli O, et al. Off-label

prescription of antineoplastic drugs: an Italian prospective, observational, multicenter

survey. Tumori 2009 Nov-Dec;95(6):647-51.

4. Leveque D. Off-label use of anticancer drugs. Lancet Oncol 2008 Nov;9(11):1102-7.

5. Dresser R, Frader J. Off-label prescribing: a call for heightened professional and

government oversight. J Law Med Ethics 2009 Fall;37(3):476-86, 396.

6. Minghetti P, Palmieri I, Selmin F. When authorized medicinal products are not available:

possible alternatives to meet legitimate expectations of patients. JPHSR 2010;1:107-12.

7. Abernethy AP, Raman G, Balk EM, Hammond JM, Orlando LA, Wheeler JL, et al.

Systematic review: reliability of compendia methods for off-label oncology indications. Ann

Intern Med 2009 Mar 3;150(5):336-43.

8. Stephen R, Knopf K, Reynolds M, Luo W, Fraeman K. Off-label Use of Oncology Drugs in a

Community Oncology EMR Database. International Society for Pharmacoeconomics and

Outcomes Research (ISPOR) 14th International Meeting; Orlando, FL 2009

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Figure 1 – Summary of Results

n=448 Protocols Containing 82 different drugs

across 15 tumour groups

Licensed Protocols

= 256 (57.1%)

Off-Label Protocols

= 189 (42.2%)

Unlicensed Protocols = 3 (0.7%)

Based on evidence-based treatment

guidelines 132 (69.9%)

Based on Phase II or III trial publications 39 (20.6%)

Based on low levels of evidence

18 (9.5%)

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Table 1 – Summary of off-label protocols (by tumour stream) and the level of evidence to support their use

Tumour Group Total no. of protocols

No. of off-label

protocols (%)

No. of off-label

protocols based on

established treatment guidelines

(%)

Total No. of off-label protocols based on primary

research reports

(Phase III or lower) (%)

No. of off-label

protocols with no

evidence for their

indication (%)

Breast 68 10 (14.7) 10 (100) 0 (0) 0 (0) CNS 15 11 (66.7) 7 (63.6) 4 (36.4) 0 (0)

Genitourinary 22 8 (36.4) 7 (87.5) 1 (12.5) 0 (0) GI 60 32 (53.3) 23 (71.9) 3 (9.4) 6 (18.7)

Gynaecological 31 16 (51.6) 11 (68.8) 2 (12.5) 3 (18.7) Head & neck 32 25 (78.1) 24 (96) 1 (4) 0 (0) Leukaemia 35 5 (14.3) 4 (80) 1 (20) 0 (0)

Lung 25 15 (60) 14 (93.3) 1 (6.7) 0 (0) Lymphoma 74 20 (27) 12 (60) 5 (25) 3 (15) Mobilisation 2 2 (100) 0 (0) 2 (100) 0 (0)

Myeloma 18 7 (38.9) 4 (57.1) 1 (14.3) 2 (28.6) Other 2 1 (50) 0 (0) 1 (100) 0 (0)

Sarcoma 26 14 (53.9) 8 (57.1 6 (42.9) 0 (0) Skin 19 12 (63.2) 7 (58.4) 1 (8.3) 4 (33.3)

Transplants 19 11 (57.9) 1 (9.1) 10 (90.1) 0 (0)

Total 448 189 (42.2) 132 (69.9) 39 (20.6) 18 (9.5)