Restrictions on use of the new drug also may be imposed by reimbursement agen- cies or third-party payers beyond those imposed by the licensed indication, and these restrictions are likely to vary by jurisdiction. For example, use of the new drug may be restricted to patients with a specific level of severity of the condition, based on a finding by a health technology assessment agency that the drug was only cost- effective within these specific severity categories. In countries with health technol- ogy assessment agencies that make recommendations about the use of or reimbursement for new drugs approved for marketing within a specific indication, it is not uncommon for these agencies to recommend reimbursement for only a sub- group of the patients covered by the marketing indication or to not recommend use of the new drug at all despite marketing approval. The frequency with which this happens varies from jurisdiction to jurisdiction. For example, a study of recommen- dations by the UK National Institute for Health and Care Excellence (NICE), the Australian Pharmaceutical Benefits Advisory Committee (PBAC), and the Canadian Common Drug Review (CDR) (Clement et al. 2009) showed that, respectively, only
Box 2.2. Difference in Approved Marketing Indication for a New Drug
Drug USA indication UK indication
Natalizumab Multiple sclerosis:
monotherapy for patients with relapsing forms of MS Crohn disease: adult patients for whom conventional therapies and TNF-α inhibitors have failed
Multiple sclerosis: monotherapy for highly active relapsing-remitting MS despite treatment with a beta-interferon or glatiramer acetate or for those with rapidly evolving severe relapse-remitting MS Crohn disease: not indicated Liposomal
doxorubicin
AIDS-related Kaposi sarcoma after failure of prior systemic
chemotherapy or intolerance to such therapy
AIDS-related Kaposi sarcoma in patients with low CD4 cell counts (< 200 CD4 lymphocytes/mm3) and extensive
mucocutaneous or visceral disease. May be used as first-line systemic chemotherapy or as second-line chemotherapy in patients with disease that has progressed with, or in patients intolerant to, prior combination systemic chemotherapy comprising at least two of the following agents: a vinca alkaloid, bleomycin, and standard doxorubicin (or other anthracycline) AIDS acquired immune deficiency syndrome, CD4 cluster of differentiation 4, MS multiple sclerosis, TNF-α tumor necrosis factor alpha, UK United Kingdom, USA United States of America
S. Wolowacz et al.
87.4, 49.6, and 54.3% of submissions of new drugs approved for marketing were recommended for reimbursement. More recent studies of NICE and PBAC recom- mendations (Mauskopf et al. 2013a, b) found that only 77.8% (NICE) and 58.8%
(PBAC) of new drugs with marketing approval were recommended for reimburse- ment. Moreover, restrictions that reduced the size of the indicated population were proposed in 55% (NICE) and 30.7% (PBAC) of those recommended.
In Box 2.3, we present examples of differences between marketed indications and NICE recommendations for use in the UK National Health Service.
In the USA commercial health-care system, where payer coverage decisions are made by managed care organizations and their pharmacy benefit managers, the reimbursement eligible population can be limited in the indicated population through prior authorization requirements for certain patients and by “step edits,”
which require a course of a generic or preferred treatment to have failed before the patient is eligible for the new drug. In Box 2.4, we present examples of step edits for drugs for lipid reduction or diabetes for a USA health plan.
Box 2.3. Examples of NICE Restrictions Within Licensed Indications
Licensed indication NICE recommendation
Ofatumumab in combination with chlorambucil or bendamustine has a marketing authorization in the UK for treating chronic lymphocytic leukemia in people who have not had prior therapy and who are not eligible for fludarabine-based therapy
NICE gave a restricted recommendation for use of ofatumumab only in
combination with chlorambucil and only for patients within the licensed indication for whom bendamustine treatment is not suitable (NICE 2015a)
Sacubitril valsartan has a UK marketing authorization for the treatment of symptomatic chronic heart failure with reduced ejection fraction
NICE gave a restricted recommendation for use of valsartan as an option for treating symptomatic chronic heart failure with reduced ejection fraction, only in people:
• With New York Heart Association class II to IV symptoms
• With a left ventricular ejection fraction of 35% or less
• Who are already taking a stable dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (NICE 2016)
Vortioxetine has a marketing authorization in the UK for the treatment of major depressive episodes in adults
NICE gave a restricted recommendation for use of vortioxetine as an option for treating major depressive episodes in adults whose condition has responded inadequately to two antidepressants within the current episode (NICE 2015d) NICE National Institute for Health and Care Excellence, UK United Kingdom
18
Box 2.4. Step Edits for Drugs for Lipid Reduction and Diabetes in Aetna National Health Plan
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitorsa Health plan Statins
Coverage
status PA
Step editb Notes Aetna 5
Premium Tier Open Formulary 23.5 million members
Altoprev (lovastatin) 60 mg oral 24-h extended release tablet
Tier 3 No Yes Trial of one generic statin medication: atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin Atorvastatin
calcium 80 mg oral tablet
Tier 1 No No
Crestor (rosuvastatin) 40 mg oral tablet
Tier 2 No No With availability of generic rosuvastatin, the brand- name drug may be covered at a higher nonpreferred co-payment and/or added to the Formulary Exclusion List. Branded rosuvastatin may also be subject to precertification and/or step therapy
Lescol (lovastatin) 40 mg oral capsule
Tier 3 No Yes Trial of one generic statin medication: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin
PA prior authorization
aRepresentative sample; not all are shown here
bStep edit/step therapy requires members to try a first-line medication, usually a generic first-tier therapy, first
Dipeptidyl peptidase-4 (DPP-4) inhibitors Health plan DPP-4 inhibitor
Coverage
status PA
Step edita Notes Aetna 5
Premium Tier Open Formulary 23.5 million members
Januvia (sitagliptin) 100 mg oral tablet
Tier 2 No No
S. Wolowacz et al.