When the first oral targeted therapy Otezla (apremilast), a PDE4 inhibitor developed by Celgene, for treating psoriatic arthritis received marketing authorization from the European Commission in 2015, industry analysts didn’t immediately paint its European market as rosy as its U.S market.1 This conservative gesture was warranted by the additional heath technology assessments conducted at the regional and national levels to control market access in Europe. Of these assessments, the one conducted by the National Institute for Health and Care Excellence (NICE) in the United Kingdom demands strong evidence of cost effectiveness for a positive recommendation and thus is often considered the last hurdle to enter the EU market among drug developers.
In December 2015, NICE published guidance that did NOT recommend the use of apremilast for treating active psoriatic arthritis. Not surprisingly, the low clinical effectiveness and premium price of Otezla were the main culprits for the negative appraisal. The guidance concluded that apremilast was not a significant change in treatment, and the associated incremental cost-effectiveness ratios were substantially over the level the agency normally accepts. The guidance also noted that the overall benefit was reduced by using apremilast before TNF-alpha inhibitors, and the use of treatment sequence with and without apremilast rather than a single comparator in Celgene’s economic model was not common practice and needed more supporting evidence. Moreover, interpretation of the long-term data, after 24 weeks, in all three trials was challenging. Although Celgene subsequently provided clarification, the long-term data remained controversial. Another significant critique is the lack of objective radiographic assessments in any of the three trials; thereby measurement of disease progression exclusively relied on HAQ-DI assessment, a patient reported outcome on quality of life. On the flip side, the guidance recognized the unmet need for access to treatments that have a different mechanism of action than TNF-alpha inhibition and the possibility that apremilast could be prescribed before a TNF-alpha inhibitor.1
Following NICE’s publication, Celgene responded by tweaking its economic model and providing a significant incentive–a patient access scheme–for NICE to conduct a rapid review in mid-2016. In December 2016, NICE released the final appraisal determination of this rapid review and claimed that:
Apremilast, alone or in combination with disease-modifying antirheumatic drugs (DMARDs), is recommended as an option for treating active psoriatic arthritis in adults only if:
- they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and
- their disease has not responded to adequate trials of at least 2 standard DMARDs, given either alone or in combination and
- the company provides apremilast with the discount agreed in the patient access scheme.
Treatment should be discontinued in people whose psoriatic arthritis has not shown an adequate response using the Psoriatic Arthritis Response Criteria at 16 weeks. 2
Celgene has succeeded in obtaining national reimbursement for apremilast in the UK despite overwhelmingly negative comments in the last appraisal report. The new appraisal report was consistent with the last one claiming that apremilast was not a significant change in treatment and was the least effective active treatment. The review committee also raised questions about whether a post-TNF-alpha inhibitor scenario should be included in the economic model. Although the newly minted patient access scheme for apremilast absolutely contributed to the outcome to a large degree, one wonders if that is all.
Here are 5 tactics Celgene employed to influence NICE:
1. Don’t focus on what you can’t change: It is almost impossible to draw different conclusions on drug efficacy without conducting additional studies. Therefore, Celgene had to change the other factor in the cost-effectiveness equation (i.e., price) through a patient access scheme, which is a non-disclosed discount to the list price of apremilast.
2. Reposition your drug: With premium pricing gone, the company likely needed to modulate the tone about the drug. In this case, a smart move is to demonstrate significant cost savings per quality-adjusted life-year loss. It turns out a low cost per quality-adjusted life-year gained is not the only way to justify NICE’s recommendation, a strategy that may be still difficult for apremilast even with the patient access scheme. After all, the cost-saving strategy can better leverage convenience in apremilast’s oral formulation, an economic benefit difficult to quantify, because “some patients may be willing to accept a certain level of reduced effectiveness” owing to apremilast’s unique oral formulation, compared with that of TNF-alpha inhibitors and ustekinumab. 2
3. You need a bulletproof economic model: The economic model is the core of any economic study; you simply cannot pass NICE without a solid model with tested assumptions and supporting data. Celgene came back with a revised economic model and provided more data on various assumptions. Although it doesn’t change the fact that some measurements were not carried out in the trials and some details of the trial design were not optimal, a thorough economic study together with a patient access scheme did work in favor of Celgene.
4. Voices from professional associations and foundations count: Comments from invited consultees and commentators contribute an important part of the evaluation process. The Psoriasis Association, British Society for Rheumatology, and Psoriasis and Psoriatic Arthritis Alliance all took part in the conversation and spoke in favor of apremilast. Many certified professional organizations like these receive financial support from drug companies to increase disease awareness and advocate for the patients. Therefore, it is wise for drug makers to maintain a good relationship with such professional associations and foundations.
5. To encourage positive public comments through the NICE website: Two out of three public comments through the NICE website were from rheumatologists who disclosed a financial relationship with Celgene. It is no secret that drug companies pay consultant fees to key opinion leaders or provide funding to and collaborate with investigators. Those who interact with the drug companies more often tend to have more experience with the drug of interest. Thus, it is not surprising to see comments coming from people with financial ties to the drug company.
We have published a 10-year market forecast for apremilast in psoriatic arthritis and conducted primary research to understand how likely physicians are willing to prescribe apremilast compared with other drugs.3,4
 Apremilast for treating active psoriatic arthritis. Accessed Jan 2017
 Apremilast for treating active psoriatic arthritis [ID1017]. Accessed Jan 2017