This letter was sent to Health Canada and Provincial Drug Plans to express some concerns CADDAC had regarding the substitution of a generic medication in place of Concerta, especially if patients were not informed.

"22 February 2010

Dr. Supriya Sharma
Director General
Therapeutic Products Directorate
Health Canada
1600 Scott Street
Ottawa, Ontario, K1A 0K9

Dear Dr. Sharma:

Re: Novo-Methylphenidate -ER-C (Novo-Methylphenidate ER-C)
Concerns of CADDAC

The purpose of this letter is to express concern about the availability of Novo-Methylphenidate ER-C.  We ask you revoke the Notice of Compliance (NOC) for this product until you are able to request additional data to unequivocally demonstrate the comparability of Concerta® and Novo-Methylphenidate ER-C.  If you are unwilling to revoke the NOC, we ask that you suspend it until a Risk Management Program (RiskMap) is put in place to prevent abuse of Novo-Methylphenidate ER-C.

Our concern is that patients who are currently being successfully treated with Concerta®  will be switched with or without their knowledge, or permission, to a generic medication that does not offer identical coverage. Inadequately treated ADHD offers a host of well  documented risks, especially if the risk is not being adequately monitored due to an unrecognized change in medication.  
 
CADDAC is a national, not-for-profit organization providing leadership and support in education and advocacy for ADHD organizations and individuals across Canada.  CADDAC will be celebrating it’s 5th anniversary in June 2010.  You can find out more about CADDAC at www.caddac.ca.

ADHD is the most treatable childhood mental health disorder.  As such, it is important that patients have access to high quality medications for the treatment of ADHD.  Medication is an important component of a successful treatment plan along with other interventions such as tutoring, counseling and education about their disease.  It is our belief that the safety, efficacy and effectiveness of ADHD medications must be unequivocally demonstrated scientifically prior to children and adolescents having access to them.  The long-term consequences of inadequate treatment are too high from a societal point of view.  Should you wish to have more information on the long-term consequences of ADHD, CADDAC would be pleased to meet with you.
Our concerns with Novo-Methylphenidate ER-C are twofold.

1.Efficacy:  Evidence to demonstrate true clinical bioequivalence has not yet been generated.

2.Safety:  The Novo-Methylphenidate ER-C formulation could represent a step backwards in patient care in that no abuse potential studies have been conducted.  There is a potential for abuse which is not present with the innovator product.

Efficacy:   Evidence of bioequivalence

Prior to the availability of Concerta® in Canada, the only formulations of methylphenidate available were immediate release and a so called sustained release formulation.

One of the hallmarks of ADHD is forgetfulness.  Therefore, multiple daily doses of medication created significant problems in the overall treatment plan.  Doses forgotten led to a lack of effectiveness of the product.  Adherence to a methylphenidate tid dosage regimen by a child, adolescent or adult with ADHD is extremely difficult. 

Even when a child, adolescent or adult remembered to take their medication 2 or 3 times per day (as prescribed), there were still therapeutic gaps.  The time periods of the therapeutic gaps not only resulted in problems and school (or work) in terms of performance but also impacted mood.

The so called sustained release formulation has so much intra-subject variability that it is virtually unusable.

The availability of Concerta® was a significant improvement in treatment from and efficacy, effectiveness and safety point of view.  Patients were able to achieve continuous coverage throughout the day without therapeutic gaps and emotional liability, leading to improvements in and consistency of academic effort.

Although Novopharm has met the threshold for bioequivalence set out by Health
Canada, the method to demonstrate bioequivalence was devised before the OrosTM technology used in Concerta® was available.  Health Canada’s various guidances on bioequivalence did not anticipate such a product and therefore, the requirements do not necessarily apply in this case from a scientific point of view.  A scientific analysis should be conducted to determine whether the current requirements are sophisticated enough to discern potential differences in this type of product.

We are not aware that Health Canada consulted with its own Expert Advisory Committee prior to issuing the NOC for Novo-Methylphenidate ER-C.  We are not aware that this product has been approved in any other country.  It is not listed on either the EMEA or FDA websites.  In fact, it appears that the FDA will require additional data before approving such a product.

Based on the information provided in the Product Monograph for Novo-Methylphenidate ER-C, the time to peak concentration occurs at 4.6 hrs with Novo-Methylphenidate ER-C, three hours earlier than the 7.6 hrs with Concerta® (in a non-fasting state).  Although the relative mean of the Cmax is less than 125% of the innovator, the upper limit of the confidence interval does not (126.17%).  Do these anomalies impact on blood levels throughout the day? It does not appear that it has been demonstrated that there is continuous coverage throughout the day without any therapeutic gaps.  The sponsor should be requested to demonstrate the clinical impact this has on children, adolescents and adults in school and work environments.

The Product Monograph for Novo-Methylphenidate ER-C does not adequately explain the release mechanism. The Clinical Trial section does not describe any clinical testing done in a laboratory classroom to determine the reliability or inter-individual variability. As noted above, previous experience with release mechanisms, such as Ritalin SR®, has demonstrated that the pharmacokinetic profile does not guarantee reliable release in all patients. The Cmax of the Novopharm product indicates that the course of release over the whole day is distinct from the Innovator drug and, in this case, that may mean children or adults taking it will have altered response at different time periods.

Bioequivalence data in children and adolescents was not generated.  Therefore, the rate and extent of absorption in a large proportion of patients has not been investigated at all.

Provincial authorities should request additional clinical pharmacology (such as partial AUC) and if scientifically warranted based on partial AUC data, clinical trial evidence to establish the actual comparative effectiveness of the two products throughout the duration of action of the innovator product to ensure continuous coverage for the patient.

Abuse potential

One of the important improvements to the treatment of ADHD brought about by the introduction of Concerta® was the reduction and/or elimination of abuse potential.  The target patient population is at risk from several viewpoints.  There is a strong genetic link in ADHD; therefore it is possible that a parent or parents are also affected.  Many parents were never diagnosed and suffer the consequences of long-term complications of untreated ADHD.  One of these complications is drug abuse.  In addition, children and adolescents in possession of a format of MPH that has abuse potential could be targets of those who wish to abuse this drug.  Finally, some patients may choose to abuse MPH themselves.  The advantage of Concerta® is that it makes this virtually impossible.  The Novopharm product uses a long-acting release system that is not the same Oros™ Technology found in Concerta®. The Novopharm product is a tablet.  A crushable tablet is more likely to have abuse and diversion potential and may put patients at risk. Novo-Methylphenidate ER-C is comparable to other short acting psychostimulant medications in this regard.

Frankly, CADDAC is surprised that Health Canada would issue a NOC for any methylphenidate containing treatment for ADHD without requiring abuse potential studies.   Therefore, if Health Canada intends to continue to allow Novo-Methylphenidate ER-C to be freely sold in Canada, a RiskMap should be put in place to prevent abuse.  The same consideration should be made for immediate release and sustained release methylphenidate products such as Ritalin and generics; Ritalin SR and generics.  The RiskMap should be designed to ensure families at risk are not in possession of, or are forced by provincial formularies to use formulations of methylphenidate with abuse potential.

Conclusion

In principle, CADDAC does not object to generic drugs and in fact for many families, a lower cost alternative would relieve a financial burden.  However, substituting generic medication without first confirming the medication has the same clinical impact and can be used safely (vis-à-vis abuse potential) is irresponsible.
 
The mechanism of action (release mechanism) of Novo-Methylphenidate ER-C and a granular understanding of the profile of action are unknown.

The abuse potential of Novo-Methylphenidate ER-C is unknown.

There is currently no evidence to show the comparability of the two products throughout the school (or work) day.

Therefore, it is the position of CADDAC that the NOC for Novo-Methylphenidate ER-C should be revoked until these very important questions are adequately addressed with scientific evidence.

I would be please to discuss these issues with you or one of your staff.  In advance, we would like to thank you for any efforts you will be able to make to support patients with ADHD and their families.

Sincerely,


Heidi Bernhardt
National Director, CADDAC"