Why do we need new formulations of old drugs for new indications?
February 17, 2015
In 2014, according to a recent press release, the European Medicines Agency (EMA) recommended 82 medicines for human use. Of these, 57 are described as being “new medicines” (of which 17 are for orphan diseases), 21 are described as “generic, hybrid and informed consent applications”, three are biosimilars, and one is for paediatric use (a Paediatric Use Marketing Authorisation or PUMA). However, by my count only about half of the 82 contain completely new medicines; the rest are either single or combination formulations of medicines that have previously been marketed. The accompanying table contains some information about the formulations that the EMA mentioned in the press release, which gives little information about the medicines themselves. Of course, a press release is not suitable for giving large amounts of information about new medicines, but as I assembled the table I realised that an important point arises from the EMA’s announcement.
The EMA refers to all the new products by their brand names. But the non-proprietary names tell you things about formulations that the brand names generally don’t. For example, could you tell from the brand names alone that three of the new products listed in the EMA’s press release, Cyramza, Gazyvaro, and Sylvant, contain monoclonal antibodies (ramucirumab, obinutuzumab, and siltuximab)? Or that four of them, Daklinza, Exviera, Harvoni, and Viekirax, contain antiviral drugs? Or that of the 82 new formulations, 22 are combination products? Or that about half are compounds that have previously been marketed under different brand names? The non-proprietary names tell you that straight away. It should be routine practice when referring to drugs either to use the non-proprietary name only or a combination of the brand name and the non-proprietary name.
Now consider the case of a new product called Hemangiol (Hemangeol in the USA). It is obvious to anyone with a smattering of Greek and to most health-care professionals, whether they know Greek or not, that this product has something to do with blood vessels. And indeed the indication for this new formulation is the treatment of proliferative haemangiomas in infants. But what the brand name hides is that this new formulation, an oral solution, contains nothing other than an old friend, the beta-blocker propranolol.
Propranolol has been used to treat infantile haemangiomas since the accidental discovery in 2007 that it was efficacious in a child in whom it was used to treat hypertrophic cardiomyopathy. But none of the liquid products currently available has hitherto been licensed for this indication. Christine Léauté-Labrèze, of Bordeaux University, the first author on the original paper in the New England Journal of Medicine, is quoted as having said that the licensing of Hemangiol–propranolol “provides a legal framework that protects the child, family members and the prescribing practitioner”. This is because the prescription of an unlicensed formulation might, for example, make a practitioner more susceptible to litigation if harm to the child resulted and might divert liability from the manufacturer. Indeed, in its “Guidance on the hierarchy for the use of unlicensed medicines” the MHRA states that “an unlicensed product should not be used where a product available and licensed within the UK could be used to meet the patient’s special need”. Thus, when Hemangiol–propranolol becomes available in the UK, prescribers will have to prescribe it rather than any other liquid formulation that is licensed for use in children but not licensed for the indication of infantile haemangioma. One US website quotes a price of $402.69 (£265) for 120 mL of a solution containing 4.28 mg/mL. According to the British National Formulary, an oral solution containing 5 mg/mL is available in the UK at £12.50 for 150 mL. That is a 30-fold difference. At a dose of 3.4 mg/kg/day for 6 months that could be a total cost of around £3000 per child, compared with £100. A small premium would be acceptable, but this is far too big a price differential.
This is not the only case in which an old established medicine has been used for a new indication, with the possibility of large profits. For example, in 2010 it was estimated that it cost £160 a year to treat a patient with sickle cell disease using 500 mg capsules of hydroxycarbamide (hydroxyurea) licensed for chronic myeloid leukaemia, but £14,900 a year using 1 g tablets of hydroxycarbamide licensed as an orphan drug for sickle cell disease. Bevacizumab (unlicensed) is as effective as ranibizumab (licensed) in treating age-related macular degeneration. The latter costs ten times as much as the former, and although it causes fewer adverse reactions one might regard the difference in cost as being unjustified.
In the case of Hemangiol–propranolol, one might give licences to other liquid paediatric formulations of propranolol, which was first marketed in the 1960s and came off patent many years ago, although it might be regarded as unfair to the manufacturers, who have gone to trouble of obtaining a licence; but unfair only if they were to charge a reasonable price. Furthermore, if the manufacturers of Hemangiol–propranolol have a use patent, their licence would be protected and this would not be a solution.
In 2012 the Court of Justice of the EU ruled, when the Polish government started to import generic products for off-label use, that exemption from the requirement for a market authorisation for financial reasons could not be justified. On the other hand, as Lincoln Tsang has pointed out in discussing the court’s ruling, “EU pharmaceutical law does not preclude the prescription of an authorised product for an unauthorised indication (‘off-label’ prescription) at the discretion of the doctor and at his own responsibility … [and] off-label prescription may also take place where the product authorised for a specific indication is more expensive than a similar product which has not been so authorised, in order to contain health care costs.” (Scrip, 13 April 2012).
So, when there can be no doubts about the comparable quality, safety, and efficacy of unlicensed products, as must be the case for propranolol, exemptions could easily be added to the MHRA’s guidance. However, the legal position of a prescriber who then decided to prescribe a cheaper unlicensed formulation would still be unsure until test cases emerged, and prescribers might be reluctant.
One way of negotiating prices in these cases has been vitiated by the failure of value-based pricing. Perhaps the only way to tackle this problem is to put pressure on manufacturers to lower their prices, through NICE for example.
Another approach might be to use beta-blockers other than propranolol. Topical timolol, for example, seems to be effective, and others might be tried.
One thing is for sure: this is not the only case of its kind. Nor will it be the last.
Declaration: I have no interests of any kind in companies that market formulations of beta blockers, liquid or otherwise.
Table 1. Details of 16 products mentioned in the EMA’s recent press release
| Brand name
|| Mechanism of action
||Advanced gastric or gastro-esophageal junction adenocarcinoma, as a single-agent after prior fluoropyrimidine- or platinum-containing chemotherapy
||Monoclonal antibody against vascular endothelial growth factor receptor 2, inhibiting angiogenesis
||In combination with chlorambucil for adults with previously untreated chronic lymphocytic leukaemia and with co-morbidities that make them unsuitable for full-dose fludarabine-based therapy
||Monoclonal antibody against the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes
||Relapsed or refractory mantle cell lymphoma in adultsChronic lymphocytic leukaemia in adults who have received at least one prior therapy, or first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.
||Inhibitor of Bruton’s tyrosine kinase (BTK), a signalling molecule in the B-cell antigen receptor and cytokine receptor pathways
||Unresectable or metastatic melanoma with a BRAF V600 mutation
||Inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and activity
||Ovarian, fallopian tube, and primary peritoneal cancers in women with BRCA mutations
||Inhibitor of human poly (ADP ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3), required for efficient repair of DNA single strand breaks
||Chronic hepatitis C virus infection (genotypes 1, 3, and 4) in adults in combination with other medicines
||Inhibitor of viral non-structural protein 5A (NS5A), inhibiting viral RNA replication and virion assembly
||Chronic hepatitis C virus (HCV) infection (genotype 1) in adults in combination with other medicines
||Non-nucleoside RNA-dependent RNA polymerase inhibitor
||Ledipasvir + Sofosbuvir
||Chronic hepatitis C virus infection (genotypes 1, 3, and 4) in adults
||Ledipasvir: inhibitor of viral non-structural protein 5A (NS5A)Sofosbuvir: NS5B RNA-dependent RNA polymerase inhibitor
||Ombitasvir + Paritaprevir + Ritonavir
||Chronic hepatitis C virus infection in adults in combination with other medicines
||Ombitasvir: inhibitor of HCV non-structural protein NS5AParitaprevir: inhibitor of the nonstructural protein NS3/4A proteaseRitonavir: inhibitor of CYP3A4
||Pierre Fabre Dermatologie
||Proliferating infantile haemangioma in children
||Not understood. Possible mechanisms include:· vasoconstriction;· antiangiogenic effect;· apoptosis-triggering effect on capillary endothelial cells;· reductions in VEGF and bFGF signalling pathways
||Ex-vivo expanded autologous human corneal epithelial cells containing stem cells
||Limbal stem cell deficiency due to ocular burns
||Re-establishment of a reservoir of stem cells in the eye, initiating normal corneal cell growth and maintenance
||Laboratoire HRA Pharma
||Endogenous Cushing’s syndrome in adults and adolescents above the age of 12 years
||Inhibitor of CYP enzymes in the adrenal glands, inhibiting cortisol and aldosterone synthesis
||Idiopathic pulmonary fibrosis in adults
||Tyrosine kinase inhibitor, blocking the kinase activity of vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and ß), and fibroblast growth factor receptors (FGFR 1-3)
||Prevention of phototoxicity in adults with erythropoietic protoporphyria
||A synthetic analogue of melanocyte stimulating hormone, a melanocortin-1 receptor agonist, stimulating melanin production
||Multicentric Castleman’s disease in adults who are HIV-negative and human herpesvirus-8 (HHV-8) negative
||Monoclonal antibody against interleukin-6, preventing its binding to soluble and membrane-bound IL-6 receptors, inhibiting the formation of the hexameric signalling complex with gp130 on the cell surface.
||Duchenne muscular dystrophy in patients aged 5 years and older who are able to walk
||Unclear; thought to enable ribosomal read-through of mRNA containing a premature stop codon, resulting in production of full-length dystrophin
The complete list of 82 products licensed by the EMA in 2014; the non-proprietary name is followed by the brand name in parentheses:
abacavir See dolutegravir
aclidinium bromide + formoterol fumarate dihydrate (Brimica Genuair)
aclidinium + formoterol fumarate (Duaklir Genuair)
aspirin See clopidogrel
bazedoxifene See conjugated oestrogens
brimonidine tartrate See brinzolamide
brinzolamide + brimonidine tartrate (Simbrinza)
budesonide + formoterol (BiResp Spiromax)
budesonide + formoterol (DuoResp Spiromax)
budesonide + formoterol (Budesonide/Formoterol Teva)
budesonide + formoterol (Vylaer Spiromax)
bupropion + naltrexone
busulfan (Busulfan Fresenius Kabi)
canagliflozin + metformin (Vokanamet)
clopidogrel (Clopidogrel Ratiopharm)
clopidogrel + aspirin (Clopidogrel/ASA)
cobicistat See darunavir
conjugated oestrogens + bazedoxifene (Duavive)
darunavir + cobicistat (Rezolsta)
dolutegravir + abacavir + lamivudine (Triumeq)
duloxetine (Duloxetine Lilly)
elosulfase alfa (Vimizim)
fluticasone furoate + vilanterol trifenatate (Revinty Ellipta)
folic acid (Neocepri)
follitropin alfa (Bemfola)
formoterol See aclidinium bromide and budesonide
glycopyrronium See indacaterol
indacaterol + glycopyrronium bromide (Ulunar Breezhaler)
insulin glargine (Abasria)
insulin degludec + liraglutide (Xultophy)
iron(III)-oxyhyroxide polynuclear + sucrose + starches (Velphoro)
ketoconazole (Ketoconazole HRA)
lamivudine See dolutegravir
ledipasvir See sofosbuvir
liraglutide See insulin degludec
metformin See canagliflozin
naltrexone + bupropion (Mysimba)
nonacog gamma (Rixubis)
ombitasvir + paritaprevir + ritonavir (Viekirax)
paliperidone (Paliperidone Janssen)
paritaprevir See ombitasvir
peginterferon beta-1a (Plegridy)
pregabalin (Pregabalin Pfizer)
rasagiline (Rasagiline Ratiopharm)
ritonavir See ombitasvir
rivastigmine (Rivastigmine 3M Health Care Ltd)
sevelamer (Sevelamer carbonate Zentiva)
sevelamer hydrochloride (Tasermity)
simoctogog alfa (Nuwiq)
sofosbuvir + ledipasvir (Harvoni)
stem cells [ex-vivo expanded autologous human corneal epithelial cells containing stem cells] (Holoclar)
tadalafil (Tadalafil Mylan)
umeclidinium bromide (Incruse)
umeclidinium bromide + vilanterol (Anoro)
umeclidinium bromide + vilanterol (Laventair)
vilanterol See fluticasone and umeclidinium
zoledronic acid (Zoledronic acid Teva Generics)