Italian Medicines Agency Agenzia Italiana del Farmaco

Orphan medicinal products

Orphan medicinal products

Orphan medicines are used for the diagnosis, prevention and treatment of rare diseases. In Europe, a disease is considered rare when it affects no more than 5 people per 10,000 inhabitants.

The first regulation on orphan medicines was introduced in the United States in 1983, with the enactment of the Orphan Drug Act, after which the need to formulate a legislative framework in this area became evident. In 1999 the European Union adopted the EC Regulation 141/2000 and subsequently the EC Regulation 847/2000.

These Regulations set out the criteria and procedure for the designation of orphan medicine, the granting of this status by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency – EMA, the incentives offered and, finally, the approval procedure.

To qualify for orphan designation in the EU a medicine must meet a number of criteria:

1) it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;

2) it must be intended for a rare clinical condition and its prevalence in the EU must not be more than 5 in 10,000 inhabitants;

3) no valid alternative treatment should be available, or, if such a alternatives exist, the medicine must be of significant benefit to those affected by the condition.

National legislation

National legislation

The Italian legislation has always protected trials of orphan drugs and their marketing to allow patients’ access to the best therapies available.

With an aim to accelerate the availability of orphan drugs at a local level, the Balduzzi Law (Law 189/2012, Article 12, paragraph 3) established that the pharmaceutical company holding a MA of an orphan drug can apply to AIFA for price and reimbursement as soon as the positive opinion of the CHMP is released, therefore before the granting of the marketing authorization by the European Commission.

The following paragraph 5-bis of the same article provides that AIFA shall evaluate as a priority, for the purposes of classification and reimbursement by the NHS, orphan drugs along with medicines of exceptional therapeutic relevance for which the related application was submitted together with the required documentation.

In this case, the evaluation deadline is reduced to one hundred days (so-called 'fast track authorization'). In case of non-submission within thirty days of the release of the marketing authorization of an orphan drug of exceptional therapeutic importance, AIFA requests the MAH company to submit the application for classification and reimbursement within the following thirty days.

Tools for early access to orphan drugs

In Italy, a patient with a rare disease can access orphan drugs through various legislative instruments. EMA’s centralized authorization procedure, with standard or conditional methods, is the main access rule; alternatively, in the absence of a marketing authorization for an orphan drug indicated for a rare disease, a patient suffering from a rare disease can access the medicine through one of the following procedures provided for by:

  • Law no. 648/1996, which allows the use of a medicine on a national basis;
  • Law no. 326/2003, art. 48 (AIFA 5% Fund), Ministerial Decree 8 May 2003 (so-called "Compassionate use");
  • Law no. 94/1998 (so-called “Di Bella Law”) which, differently from Law 648, governs the prescription of the medicine to the individual patient, on a nominal basis.

Independent research on orphan drugs funded by AIFA

AIFA was the first European regulatory agency to include the promotion of independent scientific research within its institutional objectives, also encouraging the development of orphan drugs through funding of non-profit clinical trials.

The Independent Research promoted by AIFA produces results and knowledge with particular regard to those pathologies which, considering the reduced incidence, often do not arouse commercial interest.

The results of the projects funded by AIFA, in the context of Independent Research, aim to generate evidence with a significant impact on the NHS and on the appropriateness of use of drugs, ensuring adequate repercussions of the scientific results. Independent Research is financed through the 5% Fund (Law no. 326/2003) and is aimed at all Italian researchers from public and non-profit institutions.

Price negotiation of orphan drugs in Italy

Orphan drugs, hospital drugs or drugs of exceptional therapeutic and social importance are evaluated as a priority, with respect to the procedures pending as of the date of the application submission, also through convening extraordinary sessions of the Committees, within the term of 100 days. Moreover, applicable legislation for these drugs provides for an additional facility, namely the right for the company to submit the application for classification and reimbursement prior to the release of their marketing authorization.

Orphan drugs excluded from deficit-lowering procedures

The Budget Law 2019 (Law 31 December 2018, no.145) has modified the methods for lowering the deficit due to pharmaceutical expenditure for direct purchases by the NHS facilities (so-called payback), providing that the distribution of the surplus of expenditure is spread over all the pharmaceutical companies that contribute to the expenditure of direct purchases on the basis of market shares.

It also provided that the orphan drugs that will benefit from the exclusion from the payback procedures will only be those authorized by the EMA, excluding the so-called Orphan Likes, the drugs entered in the Orphanet register and all the drugs that were authorized as Orphans by the EMA but whose period of market exclusivity has expired.

Medicines not included in the so-called EU List of Orphan Drugs (Community Register of designated orphan drugs) will no longer be considered as such in Italy.

AIFA makes available the list of orphan drugs, drafted in compliance with new legislation.

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