Gaucher disease and the problems in supply of imiglucerase

Gaucher disease is a rare genetic disease characterized by a deficiency in the enzyme acid beta-glucosidase, also known as beta-glucocerebrosidase, which is responsible for the metabolism of a lipid called glucocerebroside. 

The  of deficiency of beta-glucocerebrosidase causes deposition of glucocerebroside in the liver, spleen and other organs, affecting the operation of these. Untreated, the disease can be fatal. Therefore, it is imperative to provide the carriers of this disease the adequate treatment. (Learn more about Gaucher disease by consulting here the Brazilian consensus about the disease) 

The medical literature on Gaucher disease suggests two possible treatments: the enzyme replacement therapy (ERT), administered by intravenous infusion, and substrate reduction therapy (SRT), orally. The choice made by the doctor is based on the type classification of the disease and the patient's clinical condition. 

In Brazil, the Protocol and Therapeutic Guidelines Treatment of Gaucher Disease (Portaria SAS / MS n º 449 of July 8, 2002) covers only the TRE. The only product registered in Brazil with efficacy, safety, quality and scientifically proven for this category is the imiglucerase. 

However, in determining The Food and Drug Administration(FDA) in June 2009, the manufacturer of this drug reported to the Brazilian Ministry of Health (MS) the temporary suspension of its worldwide production, then centralized at the factory in Allston, United States, which was identified after a virus infection in the equipment used in manufacturing. 

Indeed, not to abruptly discontinue the treatment of 610 patients with Gaucher disease attended by the Unified Health System (SUS) and given the delays in delivery of lots of imiglucerase by the manufacturer, the MS has chosen to use its strategic stock, reassess the doses used by patients and eventually replace the supply of a medicine for imiglucerase still experimental, the taliglucerase alpha. 

It happens that, although preliminary studies with this new drug have shown promising results for treatment of Gaucher disease and the exceptional situation of supply reduction imiglucerase, physicians and patients feel insecure about the use of information because there taliglucerase regarding its effectiveness and safety - and rightly so. 

In addition, the new drug is not registered in Brazil and anywhere else in the world, even in Israel, a country where he was ordered to desenvolvido.O MS Surveillance Agency (ANVISA) an import permit emergency. The regulatory agency granted the permit after the document review phase 3 clinical trials of the drug without performing the same careful analysis that is done when it comes to application for registration of a biological product (DRC NO. 315 OF 26 OCTOBER 2005). 

It is worth mentioning also that the phase 3 clinical study presented at the time of application for emergency authorization had a duration of only nine months and was conducted with only 31 patients, and is already sated for 610 Brazilian patients with Gaucher Disease 

So the question remains - who can account for problems due to prolonged use of alpha taliglucerase? Not to mention the contraindications of the product, since the present study did not include patients younger than 18 years and risk groups such as critically ill patients, pregnant and lactating women. 

Believing in the need for transparency in the relations of consumption of products and services subject to sanitary surveillance, as well as fight for the population to have access to medicines that meet the highest standards of efficiency, safety and quality, SIVs expresses concern patients with Gaucher's Disease, understanding that the alternative found by MS is wrong and exposes the lives and safety of patients. 



About taliglucerase alpha

The taliglucerase alpha is an enzyme produced by biotechnological processes which, like imiglucerase, replaces the natural enzyme beta-glucocerebrosidase. It was developed by Israeli company Protalix BioTherapeutics and it is a therapeutic option of enzyme replacement therapy (ERT) to patients with Gaucher's disease is still under study. 

The new ERT does not have any record anywhere in the world, even in Israel, the country in which it was developed. According to public information, the registration request is still being reviewed by the FDA and other regulatory agencies. The forecast is that the authorization for marketing by the FDA only exit in the first quarter of 2011. 

However, despite its experimental character, the taliglucerase was purchased and will be distributed through SUS as a drug equivalent to imiglucerase consecrated. 

In view of reduction in the supply of imiglucerase worldwide, there are reports that the United States, European Union countries, Israel and other countries even if not registered, the taliglucerase is being given free by the manufacturer. 

However, it is urgent to emphasize that this dispensation is being done through expanded access protocol or under a nominal provision for patients, ensuring transparency of the patients before a trial, as required by medical ethics, but also ensured proper monitoring of safety data from the same while guiding physicians on product characteristics. 

Unlike what occurs in the Brazilian scenario, where doctors are advised to prescribe the drug trial, as equivalent to safe medication without the knowledge and consent of the patients, in apparent violation of medical ethics. 

In France, there were also temporary approval of taliglucerase, but it differs greatly from the commitment that ANVISA supplied the drugs in Brazil. 

First because they were given detailed guidance on the rules for the use of the drug, unlike the case of Brazil, where the MS summarized them in a few pages, and secondly, because to supply the drug, the French health agency makes a series ofrequirements as the physician's request, the patient's consent adequately informed about the risks of an experimental treatment, special monitoring of patients, among others. In short, a very different reality of Brazil. 

Besides the lack of transparency on an experimental drug that will be provided by the SUS, there is the obvious concern among experts about the safety of this "can be a good medicine but not yet completed clinical studies with a larger number of patients tothat had more security, "said the coordinator of the Institute of Genetics and Inborn Errors of Metabolism (Igeim) and geneticist at the Federal University of São Paulo (UNIFESP), Dr. Ana Maria Martins. 

In fact, as stated in the Guide to Health Care Professionals "on the use of taliglucerase for treatment of Gaucher disease developed by MS, the" efficacy of taliglucerase alpha was studied in a multicenter clinical trial, Phase III, unpublished, withduration of 9 months and included 31 patients aged ≥ 18 years (double-blind, randomized, parallel - a group of patients received 30 U / kg / infusion taliglucerase alpha, and the other received 60 U / kg / infusion) " 

It is clear that the very ANVISA not allow the registration of medicines that have not been tested in at least one hundred (100) patients, classifying them as "research." Therefore, one should ask the differential treatment that is now taliglucerase grants. 

And actually, by Article 18 of Law 6360, for a drug to be registered in Brazil is imperative that this has been recorded at least in their country of origin, which does not occur for taliglucerase, since that is not registered even in Israel, where it was developed. 

Most disturbing is that although there is no study on the taliglucerase in patients under 18 years and risk groups such as critically ill patients, pregnant and lactating women, the same "Guide to Health Care Professionals" quoted above makes no restrictions on the use of new medicine for these patients.Instead, it recommends the use of the product by these groups, even in the absence of clinical, as can be seen in the transcripts that follow: 

"Although there are no studies in children, there is no data to assume risks that outweigh the consequences of lack of medicine, which is the reason for recommending the use in this age group." 

"[...] This same reasoning applies to pregnant women and nursing mothers, physicians should evaluate the cost benefit " 


For all these reasons, the medical community sees the new ERT also has an alternative in an experimental situation, no proven efficacy and safety. There are no known contraindications, precautions, nor the risks to the possible adverse reactions, because there are still no published scientific studies on imiglucerase. 



About the agreement between the manufacturer and MS imiglucerase 

Because of the problems caused by the shortage of the drug world, the annual supply contract signed by the maker of imiglucerase and the Ministry of Health (MOH) in 2009 was fulfilled, but lots of deliveries of medicines was postponed to the beginning of this year 2010 . 

Then, the MS did not renew the contract for the year 2010 year contract for the production of the drug was not yet completely settled. 

However, the manufacturer of imiglucerase pledged to serve only part of the demand of the Ministry of Health, offering a partial delivery of consignments of drugs from September 2010.But this proposal was rejected by MS, which chose to purchase a plot of the experimental drug Taliglucerase emergency. 

Also, in a letter addressed to the association Paulista Patients with Gaucher's disease (APPDG) in October of this year the manufacturer said they have already resumed normal production of the drug and already have a party a certain amount of medicine to give to MS, and assured that in the months of November and December this year, could supply more than 80% of Brazil's - and still remains in MS option for the acquisition of the experimental drug. 



About the bad decisions of the Ministry of Health 

IsPhar believes that MS took the wrong decisions in the case of patients with Gaucher's disease. 

The first wrong decision of the ministry was not to receive the batch of the drug that the manufacturer has released imiglucerase. While this plot was not meet Brazilian demand in its entirety, the NHS could do without this drug primarily to the risk group, consisting of pregnant women, infants, children and the seriously ill, which was the recommendation of the European Medicines Agency (EMEA). 

Another misconception of MS was ignoring the fact that the manufacturer imiglucerase assured supply 80% of Brazil's product. Namely, the health ministry has totally ignored the fact that the only medication for the TRE with efficacy, safety and proven, and crimp it if, with the proper record in ANVISA, will be available for the treatment of most patients. 

The MOH is also mistaken to obtain only the product taliglucerase. As explained above, this is an experimental drug being tested was that even members of the group at risk. Now, with the possibility of acquiring the only medicine for the TRE with efficacy, safety and proven in Brazil, the Ministry had a duty to get it to prioritize this group. 

Another misconception of the Ministry of Health, and more importantly, was not to adopt any policy for clarification of the patients as to whether the product is experimental and related risks. In other words, the Ministry of Health will use the Brazilian carriers of Gaucher disease as a real guinea pigs, without the necessary consent. 

Headlines to date, interruption in the treatment of patients with Gaucher disease, which proves that the strategic stock of the Ministry of Health supplied the demand imiglucerase during the suspension of product manufacturing. However, for the continued well-patient care, the ministry should have acquired imiglucerase available on the market and have committed to purchasing that product as soon as the production was restored. 

However, it was not what occurred. Instead of treating the vast majority of patients with Gaucher's disease, especially members of the group at risk, with the best medicine available, though not entirely, the Ministry of Health decided to give a shot in the dark and turn those patients guinea pigs. 

The question that hangs in the air is, the patients with Gaucher disease are at the mercy of an experimental drug being without even having knowledge of the situation by which they pass?