preserving its benefits. It is this preservation of benefits that drives the true meaning of managing risk, as the intention of all such programs is to provide access to drugs for appropriate patients.
RiskMAPs address the needs of products that without additional risk management techniques potentially could have a risk profile sufficiently deficient to prohibit access to the drug. Often those drugs subject to a RiskMAP could not sufficiently address the risk profile within the labeling options available to it. For the majority of approved products, labeling and routine reporting requirements are sufficient to mitigate risks and preserve benefits. Such drugs as Thalomid®, Accutane® and Tysabri® would provide good examples of differing types of RiskMAPs, as each demonstrated the unique challenge a drug has in mitigating its own risk profile.
Since the advent of the FDAAA, the FDA now has statutory authority to mandate REMS to ensure the benefits of a drug outweigh the risks of using it. While on the surface some of the FDAAA regulations would appear to be redundant authorities, the FDA never had the ability, under statutory authority, to enforce risk management in the manner the FDAAA provides. New authorities include:
$1 million in a single proceeding, with exponential increases in fines over time — thus firmly placing the FDA in the role of an enforcement agency. The FDA has collaboratively worked to implement REMS and maintain access to life-sustaining drugs without significant use of the civil penalties statutes.
RiskMAPs have evolved to REMS, as REMS incorporate many of the principals of the RiskMAP guidance, but adds the new authorities that improve the FDA’s ability to enforce its requests. Table 1 includes certain products approved prior to the effective date of the FDAAA, which under the FDAAA were deemed to have REMS in effect because they already had elements to assure safe use (these elements typically appeared in RiskMAPs). 2 Specialty distributors and pharmacies working under REMS must recognize the consequences of noncompliance with REMS. The potential exists that one of such parties could be a vehicle of misbranding, thus triggering the civil penalty clauses while simultaneously exposing patients to greater drug-treatment-related risks.
TAblE 1
Generic name
Brand name
Alosetron
Ambrisentan
bosentan
Clozapine
Dofetilide
Eculizumab
Fentanyl citrate
Isotretinoin
lenalidomide
Mifepristone
Natalizumab
Smallpox vaccine, live
Sodium oxybate
Thalidomide
lotronex®
letairis®
Tracleer®
Clozaril®, FazaClo®
Tikosyn®
Soliris®
Actiq®
Accutane®, Amnesteem™,
Claravis™, Sotret®
Revlimid®
Mifeprex®
Tysabri®
ACAM2000™
Xyrem®
Thalomid®
Note: Products not currently marketing in the United States have been excluded.
As previously stated, all drugs
have a unique risk fingerprint. Some
drugs require minimal enhance-
ments provided through REMS,
while others require extensive sys-
tems to mitigate risk and balance
the risk/benefit equation. Gener-
ally, there are five levels of risk miti-
gation provided through product
labeling and REMS. They are:
should be designed to balance the
needs of the risk management pro-
gram with the commercial needs
of the drugs. Therefore, REMS can
be implemented in models that do
not achieve this appropriate bal-
ance; thus, the idea of a zero sum
model is not compatible with the
tenets of good risk management, as
some risk is inherently acceptable
in order to maintain the balance be-
tween risk and benefit.
edge, attitudes and behaviors, or KABs, of both healthcare practitioner and patient. Since KABs can be measured through survey instruments and other statistically significant means, the effect of REMS can be ascertained, and modifications to the REMS can be implemented to continually improve the risk/ benefit equation.
• The ability to require post-
marketing studies and clini-
cal trials,
• The ability to require sponsors/
manufacturers to make safety-
related labeling changes, and
• The mechanisms surround-
ing REMS.
By including the ability of the federal government to protect interstate commerce, the FDAAA allows the FDA to prevent the introduction of a drug into interstate commerce, effectively prohibiting use of a drug nationally. If REMS was to be requested by the FDA, the drug could be found to be misbranded, if the requested REMS was not implemented to the satisfaction of the FDA.
Lastly, unlike most common functions of the FDA, under the FDAAA, the FDA can impose civil penalties for violations on the responsible person for the drug. These violations of REMS can be up to $250,000 per violation, not to exceed
1. Professional Label and Package Insert
2. REMS – Medication Guide
3. REMS – Communication Plan
4. REMS – Elements to Assure
• With Registry
• Without Registry
5. Implementation System1
Table 2 includes medications currently requiring levels of risk minimization greater than medication guides. 3 The most important tenets of good risk management are to mitigate risk and maintain appropriate access; one should not confuse the actions required under REMS to be impediments to the use of a drug for appropriately selected patients. Good REMS programs
If we take at face value that the common principal in all risk management programs is to generate an activity between patient and practitioner that has the potential to reduce risk, we can easily identify the incremental effects on access to a drug under REMS. For example, while many healthcare practitioners take extra time to discuss the risks and benefits of using a particular drug, others do not. REMS, through the use of medication guides, attempts to create a system whereby healthcare practitioners must perform an activity (namely, counseling the patient in this case) that increases the potential of reducing risk, thus decreasing the risk versus benefit in using the drug. By performing and documenting his/her actions, the healthcare practitioner can better partner with the patient to determine if the REMS drug is the best option for the patient. REMS seeks to improve the knowl-
Communication plans often are necessary for drugs requiring healthcare practitioner administration (parenteral administration). These plans typically are directed at the healthcare practitioner. The manufacturer/sponsor of the drug under REMS must create a system of active and passive methods to inform healthcare practitioners of the components of the REMS that must be shared to maintain the appropriate and safe use of the drug. For example, communication plans discuss the key patient monitoring protocols and serious adverse events, and often include the administration techniques required to safely administer the medication to the patient (i.e., IV over one hour in D5W with monitoring of blood pressure every five minutes). The manufacturer often is free to develop any tool that can reasonably communicate the REMS safety requirements to the practitioner. It is helpful that the development of such tools has been tested through
References:
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