LRG Research Program to track efficacy
On February 1, 2016, the commercial launch of the generic version of imatinib mesylate (Gleevec), for CML (Chronic Myeloid Leukemia) was approved by the FDA after the Novartis patent expiration, and will become available for the first time in the United States through Sun Pharmaceuticals. The patent expiration date for the imatinib indication for GIST is not until 2020.
Sun Pharmaceuticals was the first to file an ANDA (Abbreviated New Drug Application) for generic imatinib for CML, and is eligible for 180 days of marketing exclusivity. Generic versions of Gleevec have already been approved in other countries.
Gleevec is one of the first successful oral targeted chemotherapeutic drugs, and over the years the LRG has monitored patients and gathered data that indicates the efficacy of Gleevec and its ability to prolong survival with tolerable side effects. Generic imatinib has yet to prove equal results. To assess the efficacy and tolerability of the generic imatinib, the LRG is launching a research program to gather comparable data beyond the FDA requirement of bioequivalence.
Generic drugs must undergo the same rigorous quality control as the innovator (brand name) drug. To gain
FDA approval, a generic drug must:
- Contain the same active ingredients as the innovator drug (inactive ingredients may vary)
- Be identical in strength, dosage, form and route of administration
- Have the same use indications
- Meet bioequivalency criteria of 80 to 125 test reference ratio
- Meet the same batch requirements for identity, strength, purity and quality
- Be manufactured under the same strict standards of FDA’s Good Manufacturing Practice regulations as the innovator drug
What must be taken into consideration, however, is that some variability occurs in the manufacturing of both brand and generic drugs. The FDA limits the amount of variability, outlining acceptable standards.
Generic drugs are not required to contain the same inactive ingredients of the innovator drug. These can include flavorings, fillers and preservatives. Patients may react differently to the inactive ingredients in the generic medication. It is important to check for any inactive ingredients that you may have an allergy or sensitivity to before taking any medication.
The generic medication may also differ in size, shape, scoring, color and packaging.
Manufacturers of generics need to prove that their drug is bioequivalent to the brand name drug – showing comparable or no clinically significant difference in their bioavailability and similar times to achieve peak blood concentrations. Bioavailability is a measurement of the extent and rate of the therapeutically active medicine that reaches the systemic circulation and is therefore available for absorption at the site of action. Scientists perform pharmacokinetic tests to measure the difference between the way the brand and generic drugs are absorbed into the body. For a generic drug to be considered bioequivalent, it should meet 90 percent confidence intervals of 80 to125 percent test reference ratio. Significant difference is 20% (α = 0.05 significance level). This simply means that the generic’s bioavailability is not significantly less than the brand name and vice versa. Bioequivalence does not necessarily mean therapeutic equivalence. To be therapeutically equivalent, a drug should have the same clinical effect and safety profile. These are not demonstrated in a bioequivalence test.
The FDA reviews the bioequivalence, and all generic drugs must have their manufacturing processes and packaging and testing sites held to the same standards as for name brand drugs. (Source: FDA)
Bioequivalence does not necessarily mean therapeutic equivalence. To be therapeutically equivalent, a drug should have the same clinical effect and safety profile. These are not demonstrated in a bioequivalence test.
Most generic drugs carry a lower price than the brand name equivalent. This does not mean lower quality, but consumers should monitor information about the generic form of their medication with their physician and medical teams.
Although the patent has expired only for CML and not for GIST, there are factors that will contribute to GIST patients being switched to generic imatinib. Factors will include the patient’s personal decision in concert with consultation with their medical team, what the insurance company will cover, and the cost.
Although pricing for generics are typically significantly lower, based on preliminary information, the difference in cost for generic imatinib is within a 2.5 to 3 percent range at this time.
If your decision is to remain on the brand (Gleevec), there are several things you can do. Your physician can write the prescription as “Dispense as Written.” Inform your pharmacist that the generic indication currently is for CML, and does not include GIST. Call your insurance company to assure that they will continue to cover the name brand.
Check for updates on the Generics section of the LRG website:
Also on our website are FAQ’s and resources to help you better understand what this transition will mean for patients, including information on financial assistance and insurance.
The LRG Launches Research Program
As US patients begin taking the generic form of imatinib, the LRG will launch a research program to evaluate the impact on treatment.
A key factor in monitoring treatment effectiveness our patient registry. Joining the LRG Patient Registry enables us to collect collaborative data that may lead to more effective treatments, and eventually a cure. If you are not a member, support our efforts by signing up today at: www.liferaftgroup.org/life-raft-groupmembership-application-form/.
Members who choose to transition to generic imatinib are encouraged to participate in the LRG Generics Research Program. In collaboration with TDM Pharmaceutical Research, the study will monitor both CML and GIST patients who are on branded Gleevec and who plan to transition to generic imatinib. Learning if there is variation in drug levels for an individual who switches between brand and generic will prove to be a beneficial tool. Such monitoring can help the treating physician to provide personalized management and care in monitoring the disease and side effects. Blood level testing is a crucial tool to developing individual treatment plans. If significant differences are discovered between the brand and generic drug levels, the physician will have options that may include switching the patient back to the brand drug.
The study will involve imatinib Blood Level Testing (BLT), a method of determining the trough level, or lowest level, of the drug in the blood. Research suggests there may be a relationship between the trough levels of imatinib and clinical benefits in GIST. Numerous factors can affect this level, including body metabolism, prescribed dosage, and drug-drug interactions. Research has suggested that a level of 1100 ng/ml may be the therapeutic level, or optimal threshold for drug efficacy.1 Further research is devoted to investigating the relationship between imatinib exposure and efficacy to develop guidelines for the potential of BLT use in clinical
In order to qualify for the study:
- Patients must reside in the United States.
- Patients must allow their insurance to be billed for the testing twice (once while on brand and once while on generic).
- Patients must enroll in the LRG Patient Registry if they have not already done so.
- Please be advised that other inclusion criteria may apply.
To learn more about the research program or to enroll, please contact Michelle Durborow at firstname.lastname@example.org. You may read more on our website: www.liferaftgroup.org/generics-research-program/
For more information about this testing procedure, please contact TDM at 302-832-1008 or support@TDMRxResearch.com.
1. Demetri GD, Wang Y, Wehrle E, Blanke C, Joensuu H, von Mehren M. Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST) (abstract, oral presentation). 2008 Gastrointestinal Cancers Symposium. Orlando, January 25–27, 2008
2. Widmer N, Decosterd LA, Leyvraz S, Duchosal MA, Rosselet A, et al. Relationship of imatinib-free plasma levels and target genotype with effi cacy and tolerability. British Journal of Cancer 98:1633-1640. 2008
3. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109: 3496-3499