Medicamentos órfãos em Portugal no contexto internacional (séculos XX-XXI) / Orphan drugs in Portugal in the international context (XX-XXI centuries)

A consciência científica, clínica e pública da existência das doenças raras tem aumentado nos últimos anos. Os medicamentos denominados de “medicamentos órfãos” são aqueles que são apropriados para o tratamento de doenças raras. As doenças raras, comparadas com outras doenças, apresentam uma baixa incidência demográfica. Por esta razão, e em virtude das condições vigentes de comercialização, as indústrias farmacêuticas não apostam fortemente nos medicamentos órfãos. Os produtores não teriam oportunidade de recuperar o capital investido na investigação e desenvolvimento do medicamento. Neste estudo os autores fazem um historial dos medicamentos órfãos em Portugal tendo como fontes a legislação e regulamentação portuguesas no quadro da legislação e diretivas europeias, o papel das indústrias farmacêuticas em Portugal, a regulamentação e fiscalização realizada pelo INFARMED, IP, bem como o acesso dos doentes aos medicamentos órfãos e o papel fulcral das associações de doentes (AU)

Lurbinectedin: First Approval.

The oncogenic transcription inhibitor lurbinectedin (ZEPZELCA™) is being developed by PharmaMar as a treatment for various cancers. The drug has been granted orphan drug status for the treatment of small cell lung cancer (SCLC) by regulatory authorities in multiple countries worldwide and was approved in the USA in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The US FDA and international regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative. Clinical investigation in other solid cancers is ongoing. This article summarizes the milestones in the development of lurbinectedin leading to this first approval for the treatment of metastatic SCLC.

Historical Perspective on Clinical Trials of Carnitine in Children and Adults.

The metabolic roles of carnitine have been greatly clarified over the past 50 years, and it is now well established that carnitine is a key player in mitochondrial generation of energy and metabolism of acetyl coenzyme A. A therapeutic role for carnitine in treatment of nutritional deficiencies in infants and children was first demonstrated in 1958, and since that time it has been used to treat a number of inborn errors of metabolism. Carnitine was approved by the US Food and Drug Administration in 1985 for treatment of 'primary carnitine deficiency', and later in 1992 for treatment of 'secondary carnitine deficiency', a definition that included the majority of relevant metabolic disorders associated with low or abnormal plasma carnitine levels. Today, carnitine treatment of inborn errors of metabolism is a safe and integral part of many treatment protocols, and a growing interest in carnitine has resulted in greater recognition of many causes of carnitine depletion. Notwithstanding, there is still a lack of data from randomized clinical trials, even on the use of carnitine in inborn errors of metabolism, although ethical issues may be a contributing factor in this regard.

Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis.

BACKGROUND: Epilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations. METHODS: Quantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria. RESULTS: Within the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years). CONCLUSION: Orphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation.

History of Orphan Drug Regulation-United States and Beyond.

The US Orphan Drug Act, passed in 1982, was the first orphan drug legislation in the world. It is a law based on economic incentives making it financially possible for pharmaceutical firms to develop products for small patient populations. Since passage, many additional countries have developed orphan drug programs and many pharmaceutical firms have developed around the orphan program. Today, more than 500 drugs for rare diseases have been developed in the United States.

The Change of Reference to Post-Marketing Surveillance Based on the Sequence of Revising the Pharmaceutical Affairs Law.

The present Pharmaceutical Affairs Law (PAL) was promulgated in October 1960 and enforced in February 1961．Thereafter, PAL has been frequently revised, was renamed the Pharmaceuticals and Medical Devices Act (PMD Act) in November 2013, and the PMD Act was enforced in November 2014. It describes the change of reference to Post-Marketing Surveillance (PMS) based on the sequence of revisions of PAL for approximately 50 years. Although the purpose of PAL in 1960 was "to control and regulate drugs, quasi-drugs, cosmetics and medical devices (drugs, etc.), and to contrive proper use," it did not include rules regarding PMS. Thereafter, "to assure the quality, efficacy and safety of drugs, etc.," "to promote research and development of orphan drugs, etc." and "to regulate designated substances" were added to the purpose of PAL over a period of time. At the time of establishing the PMD Act, "to assure the quality, efficacy and safety of regenerative products, to promote their research and development, and to prevent the onset and spread of hazards to public health and hygiene through the use of drugs, etc. "was added to the purpose. Simultaneously, the matters of control and regulation using PAL were increased whenever PAL was revised. Additionally, the PMS systems, such as adverse drug reactions reporting, drug reevaluation and drug reexamination, and the Good Post-Marketing Surveillance Practice (GPMSP) regarding the enforcement standards of PMS, etc. were initiated by regulatory directions and legislated after their establishment. Moreover, an infection reporting system and early-phase pharmcovigilance, etc. were added to the PMS systems. Furthermore, GPMSP was divided into the Good Vigilance Practice (GVP) for marketing license conditions and the Good Post-Marketing Study Practice (GPSP) for enforcement standards regarding post-marketing investigations and clinical trials, and both are regulated.

Rare diseases and orphan drugs: 500 years ago.

In 1581 Rembert Dodoens wrote "Medicinalium observationum exempla rara, recognita et aucta" a Latin book about the diagnosis and treatment of disorders with a low prevalence.

Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years.

The 1983 US Orphan Drug Act has stimulated the development of new therapies for rare diseases. To provide the first comprehensive overview of orphan-designated products and their indications, this article quantitatively analyses the characteristics and distribution of orphan designations and approvals by the US Food and Drug Administration from 1983 to August 2008. Of the 1,892 orphan-designated products, 326 received marketing approval, representing 247 different drugs and more than 200 different diseases. About half of the approvals had occurred by 4 years after designation was granted. The most common patient population size for orphan designations and approvals was fewer than 10,000 patients, and cancer was the most common disease area. The implications of such findings for future development and marketing of therapies for rare diseases are discussed.

How did uncommon disorders become 'rare diseases'? History of a boundary object.

The category of 'rare diseases' has been in growing use in the fields of public health and patient advocacy for the past 15 years in Europe. In this socio-historical inquiry, I argue that this category, which appeared initially as a by-product of the orphan drug issue in the United States of America, is a boundary object. As such, it has different specific local uses: a meaningless category for physicians, it relates to the patients' experience of illness, whereas the pharmaceutical industry first considered it as being synonymous with small markets and then with innovation. Public bodies contributed to framing a common and blurred use, based on a statistical definition whose purpose was to foster co-operation between the four groups involved in the issue. In the definition process of the category of rare diseases, the key actors were the patients and public bodies, not medical professionals or the pharmaceutical industry.