Janssen-Cilag, a subsidiary of the Johnson & Johnson pharmaceutical company, has filed an application to get methylphenidate (sold as Ritalin and Concerta) approved for ADHD - Attention Deficit and Hyperactivity Disorder ... in adults.
Swedish investigator and publicist Janne Larsson argues that the drug approval Janssen-Cilag is seeking should be denied.
There are a series of grave concerns with the drug's safety, which Larssen has outlined in a letter to the European Medical agencies and the EU Commission. He argues that the pharmaceutical company has not fulfilled its obligations even to keep the drug on the market, much less expand its use to a new indication. The data on usage and side effects if available in Sweden, but Janssen and other manufacturers of methylphenidate drugs are trying to scrape by without actually having to look at or report the facts...
The text of the letter is available in a PDF file and is also copied here below.
The PDF of Janne Larsson's letter is Application-Concerta-Adults.pdf
To: EMA (all CHMP members)
Copy: European Medical Agencies
Copy: European Commission (Health and Consumer Policy, DG Sanco)
21 August 2010
Regarding Janssen-Cilag's application to get Concerta approved for adults in Europe
Janssen-Cilag (Johnson & Johnson) is now applying for adult indication (ADHD) for Concerta in Europe.
The application should be disapproved, mainly for the following reasons:
The company has not adhered to and fulfilled the conditions for continued marketing authorisation of Concerta, as advised by the EMA and decided by the European Commission 27 May 2009. [1]
The EMA and the different medical agencies in Europe must be aware of the fact that Janssen-Cilag and the other manufacturers of methylphenidate products have done nothing effective to handle the safety issues decided by the European Commission. It can be supposed that the Agency and the Commission were sincere when stating that the actions listed in the decision were conditions to be adhered to and fulfilled; meaning that if the listed actions were not done the marketing authorisation for Concerta would be withdrawn.
We are now at the point where Concerta and other methylphenidate products should be withdrawn from the market in Europe - and very far away from a situation where Concerta could be approved also for adults.
IN ANNEX IV (P. 65) TO THE DECISION FROM THE COMMISSION, CONDITIONS OF THE MARKETING AUTHORISATION [1], from 27 May 2009, we find the following points:
"Long Term Use effects
The MAHs [Marketing Authorisation Holders] committed to provide a detailed feasibility assessment for a scientifically valid, well designed and suitably powered long-term safety study to examine specific endpoints for the following outcomes:
- adverse cognitive outcomes
- adverse psychiatric outcomes (e.g. mood disorders, hostility and psychotic disorders)..."
On this point Janssen-Cilag has (together with the other manufacturers of methylphenidate, called "the Consortium") tried to obstruct the needed follow-up actions about the psychiatric harmful effects of methylphenidate. The so called Feasibility Assessment submitted by the companies is only an aggressive effort to get away from the much needed safety studies. The EMA has been asked by the European Commission to give an answer to what has been done by the Agency by reason of the now infamous report from "the Consortium"; a report saying that the companies do not intend to ("can not") do any follow-up studies in the area of psychiatric harmful effects. [2] See a full analysis of the report from "the Consortium" in the letter A request for decisive actions from the European Commission to initiate required safety actions about methylphenidate products from 5 March 2010. [3] http://jannel.se/letter_Consortium_ADHD.pdf
"Growth, Development and Sexual Maturation
MTA Study. "Effects of stimulant medication on growth in the MTA (Multimodal Treatment Study of ADHD)" follow-up, carried out by the MTA Cooperative Group. The MAHs will evaluate the final report of the study, when published, and will update the RMP [Risk Management Plan], and where appropriate the SPC/PL [Summary of Products Characteristics/Product Label], to reflect the findings."
In actual fact the relevant evidence for decrease in growth rates is already there: Methylphenidate does decrease growth rates. The relation has already been proven in the MTA study, the results after 3 years cannot be ignored (even if the manufacturers and strong drug proponents with financial conflicts of interest do their best to ignore and disprove the relation). In the MTA 3 years-follow-up we find the conclusion that the drug treated children "...show stimulant-related decreases in growth rates after initiation of treatment, which appeared to reach asymptotes within 3 years without evidence of growth rebound". [4]
"Study on sexual maturation:
a 2-year, long-term, open-label, prospective investigator initiated study in the US on 150 adolescents (12-17 years) with ADHD, to determine whether treatment with methylphenidate will prevent smoking in this population."
As for the follow-up about sexual maturation, no data have reached the Swedish Medical Agency, and it can assumed that this follow-up will take the same route as the ordered studies and follow-up in the area of Prozac for children - meaning a scandal where nothing of value is done in the end. [5]
"Cardiovascular and Cerebrovascular effects"
It is reported that no data have reached the Swedish Medical Agency about the studies listed on this point. But instead very important data about the cardiovascular effects of methylphenidate have been revealed in the government funded long-term Raine study from Western Australia. [6] The following finding in the Australian government report should be added as proof to the already known serious adverse effects in this area: "The results also indicated that between the age of 8 and 14 years there may be an effect of stimulant medication on diastolic blood pressure above and beyond the well established immediate short-term effects on cardiovascular function. The finding that consistent use of medication was associated with an average elevation 10mm Hg at 14-years of age indicates that the long-term cardiovascular implications of stimulant medication-use need to take a high priority when determining directions for future research."
"Drug utilisation studies, including evaluation of Off-Label Use/ Abuse
The MAHs commit to provide all available retrospective data on an annual review basis for the next five years in all Member States where methylphenidate is used, to allow an evaluation of changes in usage over time. Where possible, measures of usage including variables such as information on total amount used, patient age, gender, indication dose, duration of use, treatment continuity, comorbidities, concomitant medications, data on patterns of use, physician specialty will be used. This commitment will be reviewed after 5 years. In the Member States that are covered by the IMS database, the MAHs will also evaluate off-label use of methylphenidate."
This condition for continued marketing authorisation is stemming from the alarming data described in Annex II of the Commission decision:
"The significant risks of off-label use, misuse and diversion were identified from the submitted data."
"The significant risks" are already identified. If effective actions were taken by Janssen-Cilag and other manufacturers to fulfill this condition there would be significant risks that the full scope of the disastrous scene would be shown. Hence nothing effective is done in the area.
It has been very easy to prove that Janssen-Cilag has done nothing effective to fulfill this condition for continued marketing authorisation. In actual fact all the requested long-term data (5 years) could already have been collected and analysed. Instead the company (and other manufacturers) have not even started to use the very good resources available for executing this commitment.
The point of off-label use, misuse, abuse and diversion are of course crucial as regards the application for using Concerta for adults in Europe - meaning that the non-execution of the required actions on this point - and the data that have emerged - is enough for disapproving the application from Janssen-Cilag.
The fact is that Janssen-Cilag has not only not done anything effective on this point, but the company has also submitted false and misleading data to the medical authorities in Europe.
The data are as follow:
This is what should be done according to the Commission decision: "Where possible, measures of usage including variables such as information on total amount used, patient age, gender, indication dose, duration of use, treatment continuity, comorbidities, concomitant medications, data on patterns of use, physician specialty will be used." Also data about off-label use, misuse and diversion should be collected.
And the resources in Sweden give all opportunities to fulfill this requirement via the Swedish Prescribed Drug Register [7] and other important Swedish registers (like the Patient Register).
As said in Annex IV in the Commission decision: "National Competent Authorities, coordinated by the Reference Member State where applicable, shall ensure that the following conditions are fulfilled by the Marketing Authorisation Holders" (followed by the list of conditions). However the National Board of Health and Welfare in Sweden has not heard about this obligation (the Director General says the Board has not been instructed by the Government to do anything in this area) and the Medical Products Agency says it has good intentions but cannot show evidence for having done anything. Janssen-Cilag has not been instructed by these national authorities to use the very good registers and has not sought the cooperation with these authorities in fulfilling the requirement.
If used the Swedish Prescribed Drug Register could tell the FULL story about "total amount [of methylphenidate] used, patient age, gender, ... dose, duration of use, treatment continuity, ... concomitant medications, data on patterns of use" since July 2005, meaning that data for 5 years could be presented NOW.
Anyone looking for information about diversion and abuse of prescribed methylphenidate in Sweden will easily find an abundance of data. Via this link it is possible to read 103 pages (from Swedish web sites) where the Swedish "users" tell about diversion and abuse of Concerta and Ritalin. The stories are in Swedish http://jannel.se/concrit.Apr2010.pdf [8], excerpts are presented in English in Appendix 1 below.
The stories about diversion and abuse tell about a scene already out of control. Full use of the Swedish Prescribed Drug Register for the years 2005-2010 would present data verifying the stories from the "users".
Instead of providing "all available retrospective data" in this area, using for example the registers in Sweden, Janssen-Cilag (Johnson & Johnson) is presenting wildly misleading data to the medical authorities in Europe in its Risk Management Plan (RMP) from 23 November 2009. [9]
Misuse and abuse of Concerta is described in the RMP (p. 128-129) under the heading Drug Abuse and Drug Dependence. It is stated:
"CONCERTA has a unique pharmaceutical design that prohibits the dosage form from being crushed, opened, or emptied making it virtually impossible to abuse it through injection, snorting, or inhalation means. In addition, it is a long-acting prolonged-release product and high, spiking blood levels that individuals may perceive as euphoric effects cannot be achieved with an intact dosage form. Due to these characteristics the CONCERTA formulation would probably not be the preferred choice for methylphenidate abuse."
..."The limited number of paediatric reports in the postmarketing database supports that CONCERTA treatment confers a low risk of drug dependence. The formulation makes it difficult, if not impossible to effectively abuse; therefore, is not expected to have an impact with respect to overall public health."
On page 127 in RMP it is said that the total number of post marketing reports about drug abuse events for Concerta worldwide is 16 (!).
In the RMP it is stated (p. 123) under the heading Important Potential Risk: Diversion:
"Diversion is understood as the entry of illicit pharmaceutical products onto the unregulated market through a number of channels, eg, thefts of product from the legitimate supply chain, or product obtained legitimately and subsequently diverted through various means such as Internet sales."
..."A total of 3 adverse events with preferred terms of Drug diversion have been received in the postmarketing database cumulative 01 August 2000 to 10 August 2009 (BRM Report, PSUR 2009). The limited information does not allow conclusions to be made regarding this important potential risk."
Three (!) reports worldwide since year 2000?
Some data about diversion of methylphenidate in the US are however presented in the RMP, but for Europe only the following is said (p. 124):
"From a review of public information sources, it appears that there are currently no databases in place at the EU or national Member State level to directly monitor pharmaceutical product diversion in the EU."
All in all Janssen-Cilag (Johnson & Johnson) has not at all used the good Swedish registers to investigate strange prescription patterns (indicating diversion and abuse), and is presenting NO data at all about the abuse and diversion of Concerta in Europe. To make it even worse it is said that Concerta is "difficult, if not impossible to effectively abuse" and that it is "virtually impossible to abuse it through injection, snorting, or inhalation means". The data from the "users" tell another story (see Appendix 1).
It must be taken for granted that the EMA does not accept the presented misleading data in the RMP.
In the RMP it is further stated (p. 118) under the heading Potential for off label-use:
"According to IMS covering CONCERTA retail prescriptions in the 4 major European countries where CONCERTA is available (Germany, France, Spain, and United Kingdom), from January 2003 to June 2009, the vast majority (94.0%) of retail prescriptions of CONCERTA were prescribed to children and adolescents between the ages of 6 and 20 years."
This is the only information about off-label prescriptions to adults in this 319 pages long document written by a company with immense resources to investigate and present the facts about prescriptions. If they instead of presenting these misleading data would present the facts from Sweden the following would be the text: 13 948 adults (19-) got methylphenidate (mainly Concerta, Ritalin) in Sweden 2009, while 17 331 children got the same drug. Meaning that 45 % of the prescriptions for methylphenidate were for off-label use, for adults.
While Janssen-Cilag (Johnson & Johnson) presents data indicating that 94% of the prescriptions of methylphenidate 2003-2009 (in four countries) were for children - meaning this is not a problem at all, it is easy to present data showing that 45 % of the prescriptions for methylphenidate in Sweden 2009 were for adults.
Of course this is not a secret for the national authorities concerned. The question is only how it can be accepted that Janssen-Cilag (Johnson & Johnson) gives misleading, outdated information, as the data about off-label prescriptions to adults.
Data from the Swedish Medical Products Agency (for 2009) indicate that for around 1000 cases (!) Concerta, Ritalin and Strattera (the approved ADHD drugs) had no or vanishing effects and/or harmful effects, and that the prescribing psychiatrists, as the next step in the experimentation, wanted to get a license for dexamphetamine (Metamina). The applications (mainly for adults) give an abundance of evidence about the patterns of use and that the doses of methylphenidate had to be increased after a while to uphold the drug effect. They show that the prescribing psychiatrists in many cases had to move up to even stronger drugs (dexamphetamine) when it was no longer possible to increase the dose of methylphenidate. All these cases should have been reported to the Adverse Events Registry, but very few of them were. (In fact only 16 reports of adverse events for Concerta were reported to the Adverse Events Registry for 2009, while we for the same time could se hundreds of such reports for Concerta in the license applications for dexamphetamine.)
Some examples of the adverse effects reported in connection with the applications for dexamphetamine licenses were:
"...very powerful, almost physical anguish"; "severe anxiety"; "joint pain, uncommunicativeness and suicidal thoughts"; a lot of side effects; increased anxiety, even panic attacks; depression and increasing anxiety; "sudden emotional swings from high happiness to sadness and tears"; "headache, increased anxiety and memory disorders"; "sensitive, insecure, paranoid feelings implied in the higher dose"; "a lot of side effects"; "patient even at a couple of occasions had been confined to bed"; "increased aggression"; "severe side effects such as nausea, vomiting, weight loss, anxiety and depression"; "severe side effects"; "had to be discontinued at a relatively low level due to anxiety attacks"; "very difficult adverse side effects"; "developed a psychosis which led to care in our intensive care department"; "Increased debilitating anxiety"; "adverse events in form of deep depression with apathy"; "intolerable side-effects"; "got anxiety and reinforcement of aggressive feelings"; "sharp and unexpected side effects with all treatments (ranging from allergies to hallucinations)"; "severe side effects were noted"; "got psychotic experiences...Two serious suicide attempt last month"; "severe side effects such as irritability, depression of mood state"; "very strong side effects"; "more speeded up, aggressive".
See Appendix II for a long list of examples. (For appendices, please see the PDF version of this document - Application-Concerta-Adults.pdf)
It must be very clear that Janssen-Cilag (Johnson & Johnson) is not adhering to and fulfilling the conditions for continued marketing authorisation decided by the Commission. The company must be informed that the marketing authorisation for Concerta is about to be withdrawn.
It must also be very clear that the application for approval of Concerta for adults must be disapproved.
Janne Larsson
Reporter
(Snöbollsgränd 22
129 45 Hägersten, Sweden)
janne.olov.larsson@telia.com
References:
[1] The European Commission, Decision and Appendixes about methylphenidate products, from 27 May 2009; Decision and Appendixes: http://jannel.se/anx_55708_en.pdf
[2] "The Consortium", Feasibility Assessment of a Study of Long-term Effects of Methylphenidate on Cognition and Psychiatric Outcomes, 30 October 2009, http://jannel.se/Consortium_ADHD-drugs.pdf
[3] Larsson, A request for decisive actions from the European Commission to initiate required safety actions about methylphenidate products, 5 March 2010, http://jannel.se/letter_Consortium_ADHD.pdf
[4] MTA Cooperative Group (2007), Effects of Stimulant Medication on Growth Rates Across 3 Years in the MTA Follow-up, Journal of the American Academy of Child & Adolescent Psychiatry, Volume 46(8), August 2007, pp 1015-1027
[5] MHRA, Assessment Report, Post-licensing commitment to assess sexual maturation in children (Prozac), 9 September 2009. http://jannel.se/MHRA.Assessment%20Report.2009.pdf
[6] Raine ADHD Study: Long-term outcomes associated with stimulant medication in the treatment of ADHD in children, February 2010, http://www.health.wa.gov.au/publications/documents/MICADHD_Raine_ADHD_Study_report_022010.pdf
[7] Wettermark et al, The new Swedish Prescribed Drug Register--Opportunities for pharmacoepidemiological research and experience from the first six months, Pharmacoepidemiology And Drug Safety 2007; 16:726-735, http://www3.interscience.wiley.com/journal/112749905/abstract?CRETRY=1&SRETRY=0
[8] Data from Swedish discussion forums, 2007-2010. http://jannel.se/concrit.Apr2010.pdf
[9] Johnson & Johnson, Risk Management Plan Concerta, 23 November 2009, http://jannel.se/RMP-ConcertaNov2009.pdf
