Analysis of Brazilian Public Funding Process for New Biologic DrugsTania Rodrigues, Milena Izmirlieva, Gustav Ando

ObjectiveThis research aims to ascertain if Brazil’s new health technology assessment (HTA) agency—the National Commission of Incorporation of Technologies in SUS (CONITEC)— is delivering on the Ministry of Health (MoH)’s promises of transparency and assessment timelines, whilst adopting mandatory evidence requirements for new health technologies to be funded by the public Unified Healthcare System (SUS). According to legislation that created CONITEC in December 2011, the MoH has 180 days to publish a final reimbursement deliberation in the Official Gazette from the request date, which can be extended by up to 90 days. This research focuses on biologic drugs that represent 43% of MoH’s current drug expenditure, despite accounting for 5% of purchases.

MethodsSecondary research, based on 13 CONITEC final negative and positive reimbursement recommendation reports, focused on biologic medicines published between December 2011 and 12 March 2013. Reports include deliberations from a plenary assembly of representatives (including the MoH, etc.) and a public consultation. Most reports analysed only involved evaluation of a single biologic, whilst those for psoriasis and rheumatoid arthritis (RA) included several biologics at once. Data were evaluated to determine time between the reimbursement request date and final funding decision publication in the Official Gazette, type of sponsor and rationale provided for a funding rejection, and conditions attached to a reimbursement approval recommendation.

ResultsWhen funding request dates were published, the 180-day initial analysis phase deadline was met in most positive reimbursement cases. Amongst those evaluated were 3 already SUS funded medicines not part of a reimbursement request. But an extension period was used in some negative recommendations. CONITEC has delivered on transparency with publication of the rationale behind deliberations. Out of 13 final reports analysed, 6 corresponded to funding rejections involving 9 drugs. These negative recommendations included a multiple appraisal of 4 biologics for psoriasis and evaluations of golimumab for 2 indications. Most sponsors issued with negative recommendations were manufacturers. All rejected biologics were monoclonal antibodies (mAbs) for chronic conditions, except pegvisomant. CONITEC’s rejections centred on inadequate data submitted by manufacturers, ranging from clinical safety and efficacy to the economic analysis models. CONITEC wanted safety and efficacy studies with longer duration and including greater patient numbers, preferably with SUS comparators. The agency also questioned the choice of economic models submitted.

Out of 13 final reports analysed, 7 corresponded to positive recommendations involving 14 biologics. These included: trastuzumab, evaluated in 2 indications, and a multiple appraisal of 8 biologics for RA (including the 3 already funded aforementioned biologics). Sponsors of positively recommended drugs were mostly from MoH’s Secretariats, except trastuzumab for early breast cancer and the RA multiple appraisal. A judicial request for palivizumabalso also secured a positive deliberation. Funding recommendations of mAbs and the fusion protein (etanercept) were conditional on a price reduction and to prescription in line with MoH Clinical Protocols and Therapeutic Guidelines (PCDT).

ConclusionThere is an apparent mismatch between CONITEC expectations and the manufacturers’ ability to adjust to evidence requirements needed in supporting funding applications of biologics. Showing superior efficacy and safety is proving difficult, particularly compared to the outdated SUS gold standard. Lack of objective clinical evaluation criteria from CONITEC on what is more efficacious or safe is a problem. For economic evaluations, manufacturers’ use of complex models is not likely to be well received due to lack of awareness and experience from the HTA agency. Absence of clear parameters for the analysis of cost effectiveness, including the lack of a range for this threshold, is also a controversial point. There is greater transparency in CONITEC’s HTA phase, but it is absent after a positive recommendation, when the MoH ascertains how the medicine will be offered by SUS. From the biologics analysed, only trastuzumab is available to patients. A funding request requiring a complementary factor (like a diagnostic test, etc.) should consider Brazil’s regional disparities in technological infrastructure. Nonetheless, this entire process is a major advance compared to when decisions were not made public and there were no clear timelines.

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Negative Funding Recommendations

Therapeutic Indication

Active Substance

Total Time for Final Decision (Working Days)1

Type of Sponsor

Evidence Requirement Mismatch

Crohn's disease certolizumab 172 Manufacturer Inadequate safety data

Psoriasis infliximab N/A Manufacturer/State government

Inadequate safety data (including comparators and follow-up time)etanercept 189

adalimumab 180

ustequinumab 73

Wet Age - Related Macular Degeneration

ranibizumab N/A Manufacturer Inadequate clinical endpoint

Psoriatic arthritis golimumab N/A Manufacturer Inadequate patient population, efficacy, and cost-minimisation data

Ankylosing spondylitis

golimumab 183 Manufacturer Inadequate efficacy, cost-minimiza-tion, and budget impact data.

Acromegaly pegvisomant 191 Manufacturer Inadequate effectiveness, safety, and cost-effectiveness data

Source: 1Calculated using Excel’s NetworkDays function and taking into account Brazilian public holidays.

Positive Funding Recommendations

Therapeutic Indication

Active Substance

Total Time for Final Decision (Working Days)1

Type of Sponsor

Recommendation with Conditions

Metastatic breast cancer

trastuzumab N/A MoH’s Secretariat Price reduction. Molecular diagnostic testing for HER2. Commercialisation of specific presentations. Prescribed and monitored in oncology-accredited hospitals. Fulfilment of MoH’s PCDTs.

Early breast cancer

trastuzumab N/A Manufacturer/MoH’s Secretariat

Price reduction. Molecular diagnostic testing for HER2. Commercialisation of specific presentations. Prescribed and monitored in oncology-accredited hospitals. Fulfilment of MoH’s PCDTs.

Rheumatoid Arthritis

golimumab 58 Manufacturers and patient association groups.

Price reduction. PCDT update. Should not be used in association due to potential for immunosuppression and adverse events.

certolizumab 161

rituximab 83

abatacept 127

tocilizumab 83

infliximab2 N/A

adalimumab2 N/A

etanercept2 N/A

Respiratory Syncytial Virus

palivizumab3 202 Federal Regional Tribunal of Rio Grande do Sul

Significant price reduction and elaboration of PCDT.

Renal transplant -related rejection

immunoglobulin N/A MoH Secretariat In line with yet to be elaborated PCDT.

Melanoma interferon-alpha N/A MoH Secretariat In line with PCDT.

Haemophilia recombinant factor VIII

N/A MoH Secretariat In line with MoH technical guidelines.

Source: 1Calculated using Excel’s NetworkDays function and taking into account Brazilian public holidays. 2Already funded by SUS. 3The suitable patient population was expanded from premature babies with a gestational age less than or equal to 32 weeks to 28 weeks in May 2013 after an alteration of the original deliberation publication.