Value added medicines: what value repurposed medicines might bring to society?

Figures & data

Table 1. Example of cases of repurposed medicines to assess stakeholders’ perception.

Case 1	A fixed-dose combination of two products already available on the market and used as free dose combination in arterial hypertension to reduce pill burden and avoid intake errors in a highly medicated patient population.
Case 2	A self-injected subcutaneous formulation of a product already available on the market as an intravenous formulation administered only at hospital under medical monitoring in a severe inflammatory disease.
Case 3	A new formulation of a well-known chemotherapy product helping to reduce serious side effects of the original product used in many chemotherapy regimens.
Case 4	Re-positioning of a well-known product in a rare pediatric indication as an alternative to reference treatments not specifically approved in this indication.
Case 5	A new inhaled device to administer genericised products in COPD indication, with evidence of reducing inhaler errors versus current device used with these active substances.
Case 6	An extended-release formulation of a product already available on the market, reducing administration regimen from once-weekly injection to three-monthly injection in a neurocognitive disease indication.
Case 7	A therapeutic drug monitoring device in association with a known cancer therapy exhibiting a narrow therapeutic window to potentialise drug efficacy while minimizing toxicity.
Case 8	An injectable biological to be kept refrigerated that will be provided to the patients with cool bags and sharp containers (not provided with the reference product), aiming to facilitate daily usage by the patients.

Table 2. Primary research with healthcare providers/payers/HTA bodies/regulatory authorities; Stakeholders’ profiles.

Country	Perspective	Education	Organisation(s)
Austria	HTA body’s representative	Communications & psychology, PhD in social medicine	HTA body: Ludwig Boltzmann Institute for Health Technology Assessment (LBI-HTA), Vienna (academic non-profit institute, independent entity for scientific decision-making support in the health sector)
Belgium	Health insurer	PharmD	National Health Insurance: National Institute for Health and Disability Insurance (NIHDI RIZIV/INAMI)
France	Hospital pharmacist	PharmD	Public teaching hospital in Paris/hospital pharmacy
France	Physician	MD, PhD Specialty: psychiatry	Public teaching hospital in Marseille
France	HTA body representative (Ex)/physician	MD, general practitioner	Transparency Committee (French HTA, committee within French Health Authority, HAS) Private practice as GP
France/ Europe	HTA body’s representative/regulatory authority’s representative/physician	MD Specialty: dermatology/ endocrinology	Haute Autorité de Santé (HAS) European Network for Health Technology Assessment (EUnetHTA) French Medicines Agency (AFSSAPS/ANSM) European Medicines Agency EMA)
France/ Europe	Regulator (Ex)/physician	MD Specialty: cardiology/ diabetology (hospital)	European Medicines Agency (EMA/CHMP) Teaching hospital in Paris
Germany	Health insurer/proxy payer	MD (epidemiologist)	Public Physicians Association (Association of Physicians of Hessen) G-BA (Federal Joint Committee) advisor
Germany	Proxy payer (expert/advisor)	Health economist, PhD in public health	German Social Health Insurance
Italy	Physician	MD Specialty: neurologist	Public hospital in Cesena
Italy	HTA body’s representative/hospital pharmacist	PharmD	HTA body in Piedmont Region Public hospital in Turin
Italy	HTA body’s representative/hospital pharmacist	PharmD	HTA body in Sicily region Public hospital in Messina
Poland	Hospital pharmacist	PharmD	Public teaching hospital in Krakow
Poland	Physician	MD, PhD	Out-patient specialist care unit (commercial): ENEL-MED, Cracow, Poland; UNICARDIA, Cracow, Poland
Poland	Ex-HTA body’s representative	MD, PhD	HTA body: The Agency for Health Technology Assessment and Tariff System (AOTMiT), Warsaw
Spain	HTA body’s advisor	Health economist	HTA regional bodies (incl. Catalonia, Basque Country, Andalusia, Galicia)
The Netherlands	HTA body’s representative (ex/advisor)	Econometrics, health economist, PhD	HTA body: CVZ (now called ZIN (Zorginstituut Nederland))
Sweden	HTA body representative (ex/decision-maker)	Health Economist, PhD	HTA body: Dental and Pharmaceutical Benefits Agency (TLV)
Sweden	Proxy payer/HTA body (academic)	Health economist, PhD	Public University, Department of Medical and Health Sciences, Division: Centre for Medical Technology Assessment, Linköping University
United Kingdom (Scotland)	HTA body’s advisor	Health economist	HTA body: Scottish Medicines Consortium

Table 3. Nomenclatures and definitions related to drug repurposing.

Nomenclature	Definition(s)
Super generics	‘Improved version of an original drug which has lost product patent protection’. [15] Also referred to as added value generics, generic plus, innovative generics. There is a reported shift in this terminology for ‘non-generic identity’ (hybrid terminology most commonly used). [16]
Premium generics	Nomenclature defined by Daiichi Sankyo Espha (Daiichi Sankyo generics subsidiary) with the launch of ‘high value-added generic drugs’, including ‘innovations in formulation and labelling to make drugs easier to ingest and harder for patients to mistakenly or incorrectly take’. [17]
Specialty generics	Generic drugs which ‘benefit from more sophisticated technologies (such as controlled or immediate release) or from special pharmaceutical ingredients (self-molecules or biological active substances)’ [18]
Re-innovated generics	‘Products built upon a re-innovation framework between incremental and radical innovation. They improve the next generation with revised and refined features’. [15]
New therapeutic entities (NTEs)	Nomenclature defined by TEVA as ‘new specialty medicines based on known and approved chemical molecules. These molecules are reformulated, repurposed or re-engineered to be delivered in a new way to address specific, unmet patient needs.’ [19]
Enhanced therapeutics	‘Drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system.’ [20]
Improved therapeutic entities	‘Products that offer a therapeutic advantage or differ from the me-too generic product in the sense of a patient centric drug delivery or product design or simply a more efficient product design and manufacturing process.’ [21]
Incremental innovation	‘Closely related molecules with different attributes that may offer significant value in treating particular disease variants or patient segments.’ [22] ‘Process of exploring and improving radical products.’ ‘Improvements in therapeutic quality, safety, and efficacy over existing medicines.’ [23] ‘Creating minor improvements or simple adjustments in a product’s current state.’ [15] ‘Either new approved drugs created from an already existing molecule or approved modifications to existing drugs.’ There are five types of incremental innovation [24]: new dosage form: which affects the dosage route, the dosage form and the does amount; new formulation: how the chemicals in the drug are combined to produce the drug; new combination: creation of combination drugs from existing molecules; new indication: using an existing drug to treat a different condition; new active ingredient: drugs that contain the same active moiety but include a different enantiomer, racemate, salt, ester, complex, chelate, or clathrate.Also referred to as adaptive innovation [23] or marginal innovation. [25,26]
Re-innovation	‘Process of innovation and product development that occurs after a new product is launched, building upon early success but improving the next generation with revised and refined features.’ ‘Re-innovation by the generic pharmaceutical industry can be observed in drug product design, formulation, process development and manufacturing processes going back to the early stages of the product development cycle.’ ‘The re-innovative product (as compared to an incremental new product) can be defined as a product that provides new features, benefits, or improvements through existing technology.’ ‘This kind of value-added version is manufactured in a re-innovation framework. This innovative design is between incremental and radical innovation.’ [15]
Hybrid products	‘In cases where the medicinal product does not fall within the definition of a generic medicinal product as provided in paragraph 2(b) or where the bioequivalence cannot be demonstrated through bioavailability studies or in case of changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration, vis-à-vis the reference medicinal product, the results of the appropriate pre-clinical tests or clinical trials shall be provided (as per Art. 10(3) of Directive 2001/83/EC).’ [27,28]
Bio-superior products	‘Intended to have attributes that are better than the first-generation product (…) A bio-superior utilises cutting-edge technologies such as protein engineering, and novel drug formulation and delivery approaches to enable its superiority over a first-generation product, possibly improving its efficacy or safety profile or improving administration route or reducing dosing frequency.’ [29]
‘Third Sector’ drugs	‘Compared to a NCE (New Chemical Entity), a Third Sector brand uses a proven molecule, lowering time and costs in development and, depending on the innovation, reducing regulatory risk. Compared to a generic, a Third Sector brand has a certain level of differentiation by addressing a specific payer, healthcare provider or patient unmet need and can aim for a higher price and/or market share. Some Third Sector brands may also have exclusivity and patent protection of some element of the offering, for example, a unique delivery system which generics cannot copy.’ [30]
Drug repurposing	‘Includes all the re-development strategies based on the same chemical structure of the therapeutically active ingredient as in the original product.’ [9]
Drug reformulation	‘Reformulation is, by the simple definition of the term, making a particular change in the formulation of the original drug. This can be achieved by exploiting advances in formulation technology to change the release of the active substance, pharmaceutical forms, and/or route of administration but it can also concern some excipients with no impact on the pharmacokinetic parameters. No change should be incurred in the structure of the active pharmaceutical ingredient except when it is a chiral switch. … Cases where the development of a new product does not include a change in the original formulation (i.e., change of dose, package size, etc.) should also be excluded.’ [9]
Drug repositioning	‘Process of finding a new indication for a drug or compound. … New indication is distinct from the already approved/intended indication of the original product, where “distinct” implies an anatomical and/or therapeutically distinct indication referring to the 10th version of the International Classification of Diseases (ICD-10). The situation where the new indication involves a different pharmacological target (off-target repositioning) is the only exception where a new use in a similar indication will be covered by the actual definition.’ [9]
Drug re-profiling/ Drug reusing/ Drug rediscovery	‘The usage of known drugs for new diseases. The main objective of drug re-profiling is to discover methods for using approved drugs or discarded clinical candidates in the treatment of new diseases.’ [31]

Figure 1. Illustrative representation of intermediate step created by value added medicines and potential price.

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