Monthly Archives: January 2013

January 30, 2013 | By Márcio Barra

Following yesterday’s news, today the National Agency for the Safety of Drugs and Health Products (ANSM), the French national authority on drugs, announced it is going to suspend the sales of Diane-35, an acne drug also used off brand as a hormonal contraceptive.

The agency, in a press conference held today in Saint-Denis, stated that the market suspension will occur over a period of three months, allowing the roughly 315,000 women who use Diane-35 to find an alternative drug. French doctors will no longer be able to prescribe the medicine. This comes after a benefit-risk assessment on the basis of its use as an acne treatment turned out negative, said Mr Maraninchi, the agency’s director.

In Portugal, Diane-35 is sold as a short term hormonal contraceptive.

Additionally, Infarmed reports that no deaths have occurred in Portugal due to its use since it went on sale in 2009.


The Telegraph

Notícias ao minuto

January 29, 2013 | By Márcio Barra

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) will review third and fourth generation combined oral contraceptives, under recent initiatives in France against these drugs. This comes as a request from France, and is  noteworthy as it is the first time, since the implementation of the new Pharmacovigilance Regulation adopted back in 2010, that a Member State has requested the European Agency to provide a recommendation or re-evaluation of a drug.

The PRAC will review the available data on the contraceptives and evaluate if the current information on them is of quality and accurate. Information on this review will be published following the next week meeting of the Committee, on 4 to 7 February 2013.

This review follows growing media reports about venous thromboembolism (VTE or blood clots) due to use of these contraceptives. A notorious case even went to court, after a woman, Marion Larat, sued Bayer after suffering a stroke cause by a blood clot, supposedly caused by taking Meliane (a combination of gestodene and ethinylestradiol), a third generation pill. Moreover, the French Agence Nationale de Securite du Medicament et des Produits de Sante (ANSM) launched, earlier this week, an investigation into the acne drug Diane-35 (cyproterone and ethinylestradiol), from Bayer. The investigation was triggered after four deaths in France were linked to the use of Diane-35, and reports from 125 women who suffered adverse reactions. Some reports also state that this acne drug stops ovulation, and is thus used as a contraceptive. It was approved for sale in France in 1987.

For the sake of clarity, the different generations of combined pills are due to different types of progestogens used. Each combined pill has a estrogen, usually ethinylestradiol, and a progestogen. First generation progestogens are norethindrone, norethindrone acetate and ethynodiol diacetate. Levonorgestrel and norgestrel are the second-generation progestogens. Levonorgestrel is the most widely used progestogen. Third-generation are desogestrel, gestodene and norgestimate, introduced in 1980. Drospirenone is the only fourth generation progestogen, available through the pill Yasmin, from Bayer.




The third generation pill controversy (“continued”) 


January 28, 2013 | By Márcio Barra

Humira, an injectable TNF inhibitor, and the first fully human monoclonal antibody drug approved by the FDA, back in 2002

Last week, Abbott laboratories released their full year results, and the fourth quarter sales of Humira took the spotlight, showing a 23.1% increase on year-to-year earnings ($2.7 billion), and with 2012 annual sales reaching a new peak, soaring to nearly $9.3 billion. To put it in perspective, Lipitor, from Pfizer, the biggest selling drug of all time had peak year sales of $13 billion in 2006, followed by Plavix, from Bristol-Myers Squibb and Sanofi, with peak year sales of $9.3 billion in 2011. Full year-revenue for 2013 is expected to hit $10.7 billion, taking 2nd place from Plavix and nearing Lipitor sales.

If Humira will ever knock Lipitor from the top spot is another question. Humira’s patent ends in 2016, so there’s still room to grow, especially when you consider that Humira is a biological, and not a small molecule like Plavix and Lipitor, and thus doesn’t suffer the dramatic sale descend that small molecules do when their patents expire. Still, to take the number one spot from Lipitor it has to have peak sales higher than $13 billion, and with competition from the new new oral JAK inhibitor tofacitinib (brand name Xeljanz) , from Pfizer, approved by the FDA’s expert panel in November 2012, it may prove though.

Despite the good news, Abbott reported a 35% drop in fourth-quarter profit because of costs associated to the creation of its spinoff, AbbVie pharmaceuticals.


First Word Pharma

January 26, 2013 | By Márcio Barra


As a first year student in pharmaceutical medicine in Portugal, I’m very interested on how does my country behaves when it comes to clinical trials, especially since in a few months I will be giving, hopefully, my first steps in the world of drug clinical research. As my readers surely know, Portugal (and the rest of Europe) is going through a very rough economic crisis, with recession hitting all sectors of the economy and budget cuts left and right. It’s a very daunting prospect for first jobs, as unemployment just hit a record high of 16% here in Portugal.

So, my interest on how my field of training fares in Portugal is non-surprising. I have previously published two reports which provided some raw numbers on clinical trials in Portugal for the last few years, (link 1 and link 2), but they don’t explain what’s behind those numbers, and a lot of questions occur when looking:

  • Why is the number of clinical trials submitted for approval in Portugal decreasing?
  • Why is it that, year after year for the last couple of years, we have less and less clinical trials conducted in our hospital centers?
  • Why do we have so few Phase I clinical trials?
  • How does Portugal stand against other EU member states?
  • What is the reason for these numbers? Is it the hospitals? Lack of patients? Sponsors? The regulatory authority?
  • What can be done to change this trend?

As previously stated in the two reports, the number of clinical trials submitted for approval in Portugal is decreasing, with 76 trials approved in 2012. Placed against other EU countries, these numbers are very poor.

In a survey conducted by APIFARMA in 2009 to ten pharmaceutical companies who conduct a big slice of the clinical trials in Portugal, the number of active clinical trial in Portugal was lower than Austria, Belgium and the Czech Republic (countries with similar number of inhabitants).


Number of active clinical trials

Number of planned sites

Planned patient recruitment

Investment (in millions of euros)
















Czech Republic





With the lower number of trial comes lower investment from sponsors. Portugal, compared to Belgium, lost 136 million of euros in potential investments.

Another study from APIFARMA, this one still in progress, presents some preliminary data collected from 443 clinical trials conducted in 2007 to 2011, which shows light on how much money was planned to be invested in Portugal versus the money that was actually invested. The still preliminary data shows that 14 million euros were lost in that period, mostly from unsatisfactory patient recruitment.

Looking at these numbers, one wonders how a pharmaceutical company chooses where to conduct a trial? They usually look for the following factors:

  • The presence of expert investigators and opinion leaders, who can carry a trial forward and help promote the knowledge produced in a trial.
  • The market share of the country, its economic dimension, if the country is a significant player in the international economy and if he has a market that can afford the medication after approval.
  • Quality of the execution of the trial versus the cost. Pharma companies place a lot of importance on if the country has the appropriate facilities and procedures to recruit patients.  Usually, the less bureaucracy and legal hurdles a country has, the better he is at recruiting. Good approval times by the regulatory authorities and ethic committees are also a big plus.

Sucess stories

Belgium, a country with similar dimensions to Portugal, is a case of success in Europe in the field of clinical trials. It has a strong presence of initial phase exploratory clinical trials and a good number of phase III trials. Their approval times for clinical trials are extremely competitive, averaging 15 days for exploratory and 28 days for confirmatory studies (not counting clock-stop periods). Sponsors choose Belgium as a CT location because of the quality of the data produced, access to the CT sites, the mentioned approval time and the expertise of the healthcare professionals. Cost is a big hurdle in Belgium though, alongside patient recruitment rates, but major Belgium stakeholders have set up initiatives to counter these limitations.

Poland, another case of success in the European Union, is ranked 10th in the world and 1st among emerging (and CEE) markets in the number of total clinical trials, with 1,176 clinical trial sites (2008 data). In 2010 they saw 469 new clinical trial applications.  The market structure of Poland is a bit different than the rest of the world, with CROs operating the majority (70% by volume, 53% by value) of trials. What is behind this success?

  • The population size (38 million)
  • Efficient patient recruitment
  • Quality of the execution, data produced, and of the medical staff
  • Number of CRA’s assigned to each clinical trial

The efficient patient recruitment is due to the population size and the incentives provided to the patient, as better healthcare service is provided to them under a clinical trial compared to standard healthcare. Contrary to Belgium, they lack in efficient approval times for clinical trials.

Looking at the wider picture, of the 4000-5000 new clinical trials approved in the EU, Portugal has a small slice of the cake, usually 100 new trials each year. Almost all of the trials conducted in Portugal are multinational trials; few are exclusive to our territory. In other EU countries, there are a bigger number of national clinical trials. This can be justified by the low number of academia sponsored trials in Portugal (only 2% of the applications in 2012 ). As academia sponsored trials are usually smaller scale studies, the clinical trial activity in Portugal is mostly focused on phase III trials. Competition is tightening up at the moment for Europe though, with emerging economies, like the BRIC countries, providing fast patient recruitment rates and less bureaucratic red tape to companies.

Impact of clinical research

The lack of interest from sponsors to conduct clinical trials in Portugal is harmful to the country and its economy. The direct (and indirect) impacts of clinical trials in a country’s economy are very significant:

  • They contribute to the budget of a state, through paid taxes.
  • Provide alternative cost savings.
  • An additional mechanism of remuneration to investigators.
  • Employment opportunities, additional work for researchers and young physicians and economic stimuli for other supporting business.
  • Improved access for patients to better treatments; usually sponsors provide more intense care and therapy for a clinical trial patient than what a normal patient gets under the standard healthcare system. Sometimes patients can’t even afford the drug when it’s released in the market, but volunteering in a clinical trial can make it accessible.
  • Knowledge sharing and transfer of new technologies. Potential spillover effect to other areas of healthcare.

Portugal could certainly find these contributions useful in the current economic circumstances. Efforts should be done to motivate pharmaceutical sponsors to invest in Portugal and conduct clinical trials here. GSK, Lilly, and recently Pfizer closed their clinical research units in Portugal, which shows that big sponsors are simply not interest in investing in Portugal.

Portugal’s flaws

From my experiences talking with some members of the Portuguese clinical trial industry and reading interviews and reports, the low focus of sponsors to conduct trials in Portugal can be explained by a series of issues:

  • The financial contract is the first big one in Portugal. This document states the financial terms of the trial and other details, and is signed between the sponsor of the trial and the concerned sites. Moreover, it has to be approved by the national ethics committee before coming into full force. While the national legislation states that financial compensation to the investigators must be detailed in the financial contract, few hospitals in Portugal actually pay their physicians for conducting and being involved in clinical research. Thus, there is very little incentive for many physicians and other healthcare professionals to be actively involved in clinical research. Motivation is extremely important for conducting any job, and investigators should be rewarded for their effort when working in a trial.
  • The lack of a standard model for financial contracts delays negotiations between sponsors and clinical trial sites.A standard model for financial contracts, accepted and approved by all Portuguese clinical trial stakeholders would surely be helpful in reducing bureaucracy.
  • The need of approval from several ethic committees is another hurdle. In Portugal, the ruling ethic committee is the CEIC, and a study to be legal has to be approved by it. However, all public and private health institutions have what is called a CES, a local ethic committee.  What usually happens is that, while the CEIC has a 60 day period to give their evaluation, the clinical trial sites do not approve the trial without the favorable opinion of their own ethic committee, creating a kind of double ethical evaluation, delaying the trial start. Worse yet, there is no standard procedure on how the different CES conduct their evaluation. One CES may do one thing, and other CES may do something completely different.
  • CEIC is not a centralized ethic committee and thus cannot provide a single, national opinion on a clinical trial. Some structural reforms in how the Portuguese ethic committees conduct their operations are certainly needed.
  • Morevoer, Belgium’s clinical trial legislation doesn’t mention that approval from a national commission for data protection (CNPD) is needed, unlike Portugal. The more agents a sponsor needs approval from, the slower a trial starts. Streamlining is definitely in order for Portugal.
  • There are many flaws how on a sponsor requests authorization from the Portuguese national commission for data protection. Their electronic form is outdated in format, not allowing the sponsor to attach a document or annex a file in some sections, while allowing in other sections.
  • As for the low number of phase I and phase II trials, it could be due to cultural reasons and absence of proper facilities.  Before the clinical trial directive standardized the EU clinical trial landscape, the national legislation didn’t allow clinical trials to be conducted in healthy patients. Consequently, Portugal didn’t have a background in exploratory trials, until the creation of the phase I unit by BIAL.
  • Another concern is the almost nonexistence of clinical trials conducted at the initiative of academia and academic researchers. The shortage of funds and incentives to conduct clinical research makes them a tricky proposition to academic researchers. Turning this type of research into a more appealing proposition for them could potentially attract more phase I and phase II trials.
  • But it’s not just phase I trials that need proper facilities. Throughout Portugal, many hospitals are simply ill equipped to manage a clinical trial, usually by lack of a clinical trial management team, experienced physicians in clinical trials and proper standardized procedures for it’s operations. Creating specialty sites could probably help, but it’s probably something currently not on the government agenda.
  • There is also the issue of public perception. The general public and many members of the media don’t understand what a clinical trial is and the value it holds. The idea that patients who join clinical trials are guinea pigs, submitted to numerous risks is very much ingrained in Portugal, and that needs to change. The public needs to understand that a clinical trial is a way for a patient to access an innovative therapy, which may very well extend his life or get rid of a serious symptom. The media should also play a more active part in this. Promotion of clinical trials is hard enough as it is, with all its restrictions in Portugal. Changing the perception of patients would be a great boost to patient recruitment rates.

And last, there is the nagging feeling that all Portuguese stakeholders are aware of what is needed to improve the current state of clinical trials in Portugal, but a strategic agenda is still needed, to reunite all agents. Maybe someone who steps up and takes the role of a leader is necessary.


PWC study on Belgium

PWC study on Poland 

EC best practices legislation recommendations 

APIFARMA studies

January 15, 2013 | By Márcio Barra

Provenge, from Dendreon Corp., is a therapeutic cancer vaccine for prostate cancer, and an unfortunate case of a good idea panned by some bad decisions and bad timing.

This drug is the first therapeutic cellular immunotherapy that showed positive results in clinical trials, when compared to placebo, and the first ever of its kind approved by the FDA back in 2010. It’s a vaccine for late stage hormone-refractory prostate cancer ,and the basic idea behind this vaccine is to recruit the patient’s own immune system to fight off the cancer, first by extracting the patient own white blood cells, incubating them with a specific protein and injecting them back into the patient. It’s a novel idea in the field of cancer therapy, an example of the growing personalized therapy market, and has a much easier side effect profile for the patient than typical chemotherapy. It could have been a blockbuster except for one thing: its cost-benefit correlation.

Provenge therapy outline

The drug extends the survival rate by a median of 4.1 months, according to clinical trials. This number, when compared with other existing therapies for terminal prostate cancer, is on the higher end, but is not a significant improvement on other existing therapies. The light side effect profile, from its novel method of action, is the main selling point, alongside the method of administration (three infusions over 4-6 weeks, instead of typical chemotherapy therapy sessions that go on for months). But for many patients and physicians, shelling out $93,000 for a marginal improvement is a steep cost. With a high price reimbursement questions appear, lingering on the minds of physicians in clinics and hospitals, who would have to keep enormous lines of credit for treating a patient with Provenge. From what I talked with a few physicians, they would not prescribe it to a patient for cost reasons. $93,000, it seems, is too much to ask for four more months of life.

The upfront price has been the main reason for a lack of demand of Provenge since its launch in 2011.But now reports are coming in that maybe Provenge may be starting to get a hold of the 30.000 patients market (estimated at a $2.8 billion in annual sales potential). Analyst Geoffrey Porges reports that urologists expect to increase their use of Provenge up to 20% this year.  Shortly after, Dendreon Corp. inc stock grew 21%, its biggest increase since January 2012. The drug sale forecast also increased from $580 million in 2017 to $799 million. This might sign the beginning of an increase of demand for the drug in 2013, if the drug can compete with the new drug Xtandi, from Medivation, which has been getting a lot of press. Provenge-ance perhaps? (ouch) Dendreon Corp. sure needs it.


January 11, 2013 | By Márcio Barra

As promised, here’s part 2 of my article on the new European regulation for clinical trials. Please enjoy, and share if you like it!


In July 17, 2012, the European Commission approved a proposal for the creation of a regulation for EU clinical trials, entitled “Regulation of the European parliament and of the council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC” (12). If approved, it will come into force before 2016, followed by a three year period where it runs parallel with Directive 2001/20/EC, as to ease up MS transition into the new rules(12) (7). This regulation hopes to improve the EU clinical research environment for the next 20 years with the following changes (13):

Change of legislative nature


The new regulation addresses the deviating interpretations of the directive from the MS by virtue of being a Regulation instead of a Directive, being immediately applicable to all 27 MS once it comes into force. This ensures that all procedures governing clinical trials are the same between all MS, as the regulation provides a common, shared standard.


New authorization procedure


The new regulation, continuing along the lines of harmonizing all MS, proposes a new standard authorization procedure for conducting a clinical trial, where it is submitted through a new “single portal”, managed by the EC. The new authorization procedure can be summed up as two part procedure. In the first part, the sponsor submits a clinical trial application dossier (detailed in the regulation) to the intended MS (hereby referred as concerned MS) through the portal, and selects one of the intended MS as the “reporting MS”.

This reporting MS has to give a preliminary report in 6 days (whether or not the MS accepts being the reporting MS and if the trial falls into the new regulation). Afterwards, the reporting MS will carry out an evaluation of the clinical trial, focusing on details such as the expected therapeutic and public health benefits, risks for the patients and compliance with various requirements, taking into account considerations from the concerned MS. This assessment report of the trial has to be submitted to all concerned MS within 25 days for a normal clinical trial, 10 days if it’s a low intervention trial and 30 days if it’s for an ATMP.

Part II of the procedure is carried out by the concerned MS. It deals with intrinsic aspects of each MS (legislation, health culture, ethic concerns) and more technical details of the trial, like informed consent details, patient recruitment, site feasibility, trial investigator and others. Each individual MS assessment is communicated to the sponsor in 10 days from the validation date. If any deadline is exceeded, the trial will be approved as falling within the regulation. In some cases, a MS can opt out from the conclusions of the reporting MS.

Subsequent additions of new MS for a trial are also eased up in the new regulation. All they have to do is conduct an individual assessment, similar to the one conducted in part II (7) (12).


For evaluating a trial application, the current directive (1)  states that it must be conducted through each MS NCA and Ethic Committee. The new regulation however, gives the MS liberty in choosing what assessment bodies conduct the evaluation of the trial, as long as the MS safeguards that it is jointly carried out by a significant number of proper qualified professionals together with one patient and one person whose main area of interest is non-scientific.


Simplified rules for clinical trials of already authorized medicinal products

The regulation simplifies the requirements for proposing and conducting trials on already marketed drugs who pose few risks to the patients. These trials, dubbed “low intervention trials”, will have less regulatory requirements. Simplifications include short timelines for MS assessments (10 days) and sponsors aren’t obliged to provide damage compensations for clinical trial subjects (12) (7).


As previously mentioned, the regulation spares the sponsor of a low intervention clinical trial to pay indemnifications or insurance. In these cases, coverage is provided by the medical practitioner general insurance for example. For trials that require insurance, the 27 MS are obligated to set up a standard national indemnification mechanism for damages occurred to participants. It will be free of charge for studies that don’t intend to obtain data to support a MAA. This mechanism will be helpful to non-commercial sponsors when obtaining insurance coverage, something they have had difficulties since the introduction of obligatory insurance (1).

Shared responsibilities between sponsors – Co-Sponsorship

While the regulation deems that a single sponsor per clinical trial is preferable, it is aware that clinical trials are increasingly a multi MS activity, with multiple pharma companies and research institutions establishing networks. This creates difficulties when pinpointing a single sponsor, for practical or legal reasons.

This regulation introduces the concept of co-sponsorship, which allows sponsors to split responsibilities for a clinical trial among themselves. One sponsor must be designated as the main contact point with authorities. In the lack of such an agreement, all sponsors shall have full responsibility for a clinical trial.

Safety reporting

Rules for safety reporting, while still based in Directive 2001/20/EC, have been streamlined, with the most significant change regarding the annual safety reports. These have been modernized, and for drugs that are used according to their MAA, they don’t need to be submitted, as normal pharmacovigilance rules apply.



The regulation gives power to the European Commission to coordinate inspections between MS, and to coordinate the regulatory systems of non EU countries, as to ensure compliance with the new regulation and the ethical principles established in the Declaration of Helsinki.



Can the new regulation bring more stakeholders to invest in clinical research in Europe? Only the future can tell. But swift action is needed, to safeguard the well-being of clinical research in Europe.

January 10, 2013 | By Márcio Barra

(Note: this article on the new European clinical trial regulation will consist of two posts, one today, and one tomorrow or sunday. Please keep an eye out and enjoy this article. Also, please share if you enjoy it!)



Originally published in April 2001, Directive 2001/20/EC introduced the standards for conducting clinical trials in the EU Member States (hereby referred as MS) (1), building upon the concepts brought forth by the Council Directive 65/65/EEC of  January 26th 1965, which, among others, made mandatory for a marketing authorization of a medicinal product to be accompanied by a dossier containing data of the results of clinical trials conducted (2). It came into effect into 2004, after an adaptation period allowing for each MS to adopt the necessary provisions, and it shaped the EU clinical trial operations with a series of innovations and requirements, such as:

  • Rules for conducting a trial
  • Created the concept of Ethic Committee (EC), special national bodies that evaluate a clinical trial’s compliance with ethical standards
  • A time frame of 60 days for both the National Competent Authority (NCA) and EC to evaluate a clinical trial application, thus addressing time differences between different countries (3)
  • In multicenter trials conducted in multiple MS, all MS must give their permission
  • Rules for clinical trials on minors and other special populations
  • Established a database for clinical trials in Europe, EudraCT, launched in 2004 (1).

In short, since its 2004 enactment, Directive 2001/20/EC, and its accompanying piece, Directive 2005/28/EC (4) (regarding good clinical practices when conducting trials), shaped the current EU clinical trial landscape.

The Directive 2001/20/EC however, from the two public consultations executed by the EC, one from October 9, 2009 to January 8, 2010 (5) and the second from February 9, 2011 to May 13, 2011 (5), is not held in high regard by European stakeholders. From the feedback provided by patient organizations, the pharmaceutical industry, non-commercial research stakeholders and all the MS (6), it’s clear that there is still a long way to go. Directive 2001/20/EC attempted to bring to the EU a standard clinical trial submission and authorization procedure to all MS, but it was not fully successful, mostly because of its directive status – a piece of EU regulation where its provisions must be transposed by each MS into their national law. (7)

These, as pointed out in the consultations (5), led each MS to adopt different interpretations of the Directive. In a way, there are 27 different implementations of the Directive and 27 different sets of rules governing GCP, with key differences between MS on how they handle reimbursements, substantial modifications to a clinical trial, ethic committee constitution, deadlines, and other topics (3) (8).

Another hurdle occurs when a sponsor wishes to conduct a trial in more than one EU country, an increasingly more common situation, as, more than ever, clinical trials are a multinational affair (3). In those cases, as stated by the Directive (1), a sponsor has to obtain authorization from all the MS where he wishes to conduct the trial. Then, each country conducts its separate assessment of the application. With each MS having two distinct evaluating bodies (the NCA and one or more Ethic Committees), who often require MS specific submission material, it’s not uncommon for different MS to reach different conclusions, delaying the whole process (7) (9). Directive 2001/20/EC does not take into account the new clinical trials reality, and as such burdens clinical trials.

Even low risk trials, usually with already marketed drugs which pose few risks for the patients, fall into difficulties, as they are subject to the same regulatory scrutiny as higher impact trials(9).

With the growing competition from Asia (10), Europe needed to improve the procedures and quality of clinical trials conducted in Europe, and so the concept for a new regulation was born (11).

End of part 1