Plasma-derived medicinal products in Italy: information sources and flows

Introduction

For the purpose of a systematic analysis of the manufacturing, marketing and usage of plasma-derived medicinal products (PMPs), it is essential to define all stages of the medicinal product life-cycle and to properly identify all information sources suitable for detecting and quantifying the information related to the assessment of each stage.

The PMPs present some peculiarities. Their biological active substances are obtained by an industrial extraction process of human plasma derived from voluntary donations, instead of chemical synthesis. As a raw material, plasma can be a vehicle of blood born infectious diseases. Therefore, the Italian and European legislations identified several measures aimed at reducing the risk of infection, such as: donor selection, biological validation tests, methods of pathogen removal and inactivation; moreover, the adoption of prescriptive measures is envisaged in order to guarantee both traceability and pharmacovigilance of all PMPs^1–11.

Another peculiar feature of PMPs is related to the ownership of the raw material and of the derived medicinal products. In Italy, as regards the national plasma collected by Regional Blood Transfusion Services, Regions and Autonomous Provinces (henceforth referred to as ‘Regions’) retain the ownership of both of them within the toll fractionation agreements with the authorised manufacturer. On the contrary, the commercial product ownership is assigned to pharmaceutical companies, which obtain the raw material from blood establishments in all other countries where plasma provision for commercial use is allowed.

The aim of this manuscript is to provide an exhaustive critical description of all data sources available in Italy for the study and monitoring of the entire medicinal product life-cycle and then to highlight the degree of overlap of various information sources and to demonstrate the feasible analyses that might be developed using each of them.

Lyfe-cycle of plasma-derived medicinal products and data sources

All aspects of the PMP life-cycle (manufacturing, marketing and use) can be summarised as shown in Figure 1.

Figure 1.

Life cycle of medicinal products.

Source: Ministry of Health, adapted by the Italian National Blood Centre.

Every aspect of the PMP life-cycle is examined with regards to the availability of information sources and Table I summarises the information that sources can provide. Generally speaking, the data collected may be grouped by four types of information: 1) information concerning a single medicinal product: manufacturer, marketing identification code (Autorizzazione di Immissione in Commercio, AIC code), quantity of packages and related cost; 2) information concerning who prescribes the PMP: identification of physician and/or health facilities; 3) information concerning who provides the PMP: identification of health facilities or pharmacies; 4) information concerning the patient who receives the PMP: patient identification and/or other information, i.e. exemption from pharmaceutical ticket payment.

Table I.

Types of information concerning plasma-derived medicinal products registered by different information flows.

Type of information	MIF	IMS	F CONV	FED FARM	FED	FH	TRACCIA	SISTRA	Fractionator
Quantity of plasma intended for manufacturing								X	X
Manufacturer	X	X	X	X	X	X	X		X
PMP identification code (AIC)	X	X	X	X	X	X	X		X
Prescriber ID			X		X
Patient ID			X		X
PMPs Provider ID		X	X	X	X	X	X		X
Quantity	IU	IU	NHS	NHS	NHS	NHS	IU		NHS
Cost		IE*	NHS	NHS	NHS	NHS	NHS
Life-cycle stage	O	O	U	U	U	U	D	M	M
Remarks		Pharmacies distribution channel only

^*Indistinct estimate between public and private expenditure applying the retail price (gross expenditure).

Legend MIF: Marketing Information Form source; IMS: IMS Health Data source; F CONV: Flusso informativo della Farmaceutica CONVenzionata - Institutional information flow of Accredited Pharmacies; FED FARM: FEDerazioni delle FARMacie (federations of pharmacies) data sources; FED: Flusso informativo dell’Erogazione Diretta dei farmaci - Institutional information flow of the medicinal products direct provision; FH: Flusso informativo della Farmaceutica ospedaliera; FH - Institutional information flow of hospital pharmaceutical utilisation; TRACCIA: Flusso informativo della TRACCIAbilità del farmaco - Institutional medicinal products TRACEability flow; SISTRA: Sistema Informativo Servizi TRAsfusionali - Italian Blood Information System; Fractionator: toll fractionation data provided by the manufacturer within the toll fractionation agreements with Regions; PMP: plasma-derived medicinal product; AIC: Autorizzazione di Immissione in Commercio - Marketing authorisation code; ID: identifier; M: manufacturing; O: offer; D: demand; U: utilisation; IU: indistinct utilisation (public and private); NHS: public utilisation; IE: indistinct expenditure (public and private).

In Italy, there are two possible procedures for the manufacture/supply of PMPs:

1. toll fractionation agreements among PMPs manufacturers and Regions, individually or in association. Regions provide the plasma collected throughout their Blood Transfusion Services to a private manufacturer identified by means of a call for tender procedure. The manufacturer receives a remunerated service for the PMP production¹². The agreements currently in place concern the production of the following PMPs: human albumin, polyvalent immunoglobulins for intravenous administration, antithrombin, prothrombin complex concentrates, clotting factors concentrates VIII and IX.

2. Free market, where pharmaceutical companies supply their products after the definition together with the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), of the maximum reference sale price to the NHS.

Data sources related to the manufacture/supply of the medicinal product life-cycle are the following:

• - Marketing Information Form (MIF).

  All information declared by the manufacturers concerning the amount of packages produced, registration and batch number, which are made available for the Italian market in conformity with the Italian and European legislation^13,14 (Table I).

• - IMS Health Data (IMS).

  IMS is an international private society that, among other duties related to healthcare systems performance, is in charge of recording the quantity of medicinal products moved from the manufacturer or the wholesaler to pharmacies open to the public. Therefore, these data cover the specific segment of the pharmacies distribution channel (Table I).

• - Italian Blood Information System (Sistema Informativo Servizi TRAsfusionali, SISTRA).

  This is the information system of the Italian Blood Services¹⁵. Among other functions, SISTRA records the amount of both plasma produced and plasma assigned for toll fractionation (Table I).

• - Toll fractionation data.

  These data are provided by the manufacturers within the toll fractionation agreements with Regions (Table I).

In Italy, there are three possible channels of distribution that represent the demand/utilisation of PMPs:

1. Pharmacies open to the public (National Health Service Accredited Pharmacies).

   All pharmacies that can provide patients with medicinal products either by purchases funded by National Health Service (NHS), under submission of a prescription (public demand), or by private purchase (private demand).

2. Public healthcare facilities.

   An NHS facility uses medicinal products in the delivery of its services of competence and for the direct provision to patients for home utilisation.

3. Private healthcare facilities.

   A private facility, which can be also accredited, uses medicinal products in the delivery of its services of competence.

All data sources related to the demand/utilisation of the medicinal product life-cycle are the following:

• - Institutional information flow of Accredited Pharmacies (Flusso informativo della Farmaceutica CONVenzionata, FCONV). FCONV records all data related to medicinal product prescriptions and aims at monitoring the pharmaceutical services funded by the NHS provided by the pharmacies open to the public¹⁶ (Table I).

• - Federfarma e Assofarm Data (FED FARM): National Federation of private accredited pharmacies (FEDerazione nazionale unitaria titolari di FARMAcia, Federfarma) and National Public Pharmacies Association (Federazione delle Aziende e servizi socio-farmaceutici, Assofarm) collect all prescriptions from their members. This survey, which covers effectively 100% of pharmacies, should overlap the FCONV data, since the latter comes from the main source: the NHS prescription (Table I).

• - Institutional information flow of the medicinal products direct provision (Flusso informativo dell’Erogazione Diretta dei farmaci, FED). FED registers the home utilisation of medicinal products distributed by public healthcare facilities; direct provision can also occur by specific agreements with the pharmacies open to the public (toll distribution)¹⁷. In the latter case, the distinctive feature lies on the difference in product prices dispensed by the accredited pharmacies: the package remains equal, but the direct provision price is generally lower because it is equal to the hospital price established by the tender award (Table I).

• - Institutional information flow of hospital pharmaceutical utilisation (Flusso informativo della Farmaceutica ospedaliera, FH). FH detects the use of medicinal products in public healthcare facilities within the provision of their services of competence¹⁸ (Table I).

The above-mentioned information flows were separately implemented with the aim of monitoring all data related to different specific stages of the medicinal product life-cycle. They are mainly tied to the assessment of the NHS expenditure and are defined on each distribution channel.

A more general information flow is the Institutional Medicinal products TRACEability Flow (Flusso informativo della TRACCIAbilità del Farmaco, TRACCIA). TRACCIA is the Central Database at the Ministry of Health aimed at tracing the single package at each stage of distribution, from the manufacturer or the wholesaler to the pharmacy, healthcare facility (public and private) or any other organisational structures of the NHS¹⁹. TRACCIA keeps track of all medicinal product movements identified by the AIC code² and quantified by the number of packages, from one logistics site to another. According to the law¹⁹, if the final receiver is a public entity (hospital pharmacies, public healthcare facilities, etc.), also the payment due is detected along with the quantity of the product in order to monitor pharmaceutical expenditure (Table I).

Degree of information overlapping

In general, all data sources can be grouped as:

1. Pharmacies open to the public: IMS, F CONV, FED FARM, FED and TRACCIA. Flows cannot be coincident because:

   • - both F CONV and FED FARM refer to the NHS consumptions, whose data are registered when medicinal products are provided by pharmacies;

   • - IMS records the sales from the distributors and wholesalers having, as a consequence, time lag due to repository. Moreover, comparing to the above-mentioned flows, it considers private consumptions also;

   • - the total quantity of consumptions identified by TRACCIA must be equal or higher to the IMS one, because it also records the total sale quantity independently of whether the usage is at the expense of the NHS or not. However, in addition to the distributors and wholesalers, TRACCIA can detect the direct supply to the pharmacies from manufacturers and/or from the Regional Healthcare Services, i.e. the toll distribution. This latter supply is also recorded in FED.

2. Public healthcare facilities: FED, TRACCIA and FH. Flows cannot correspond since:

   • - TRACCIA records all movements connected to the purchase and it is affected by stocks;

   • - FH detects all consumptions when the medicinal products are distributed to the hospital departments.

Conclusions

In general, all the above-considered information flows are not expected to be coincident. However, comparisons between different flows is expected to respect the scalability of each distribution channel. In conclusion, in order to analyse the demand for PMPs in Italy, the TRACCIA flow was used as the reference source since it proved more suitable to quantify the total demand for PMPs. Indeed, it considers all amounts distributed to both public and private healthcare facilities and pharmacies independently from the type of distribution, namely at the expense of the NHS or not. Moreover, the TRACCIA flow was clearly the only one able to provide reliable and consistent data for the observation period considered (years 2007–2011), since its implementation dates back to 2005 and it represents the most consolidated among all information flows in the pharmaceutical field.