Opinion: What can we learn from HIV trial design?

Clinical success does not guarantee access. Let's enable better better valuation of early stage assets. 

We know that there is a gap in the number of antibiotics in the pipeline versus the medical need across the globe. We also know that when drugs do beat the odds, earn regulatory approval, and are brought to the precipice of commercialisation, they still fail to reach the people who could benefit the most (e.g. this and this). HIV drug development offers a useful lesson in how early stakeholder engagement can shape trials around the needs they must address. Planning evidence for access alongside evidence for approval could strengthen the commercial case for continued pharmaceutical investment and help clinically successful drugs reach and remain available to the people who need them most.

Clinical success does not guarantee access

In September, we saw Merck discontinue imipenem-cilastatin-relebactam (recarbrio) from the US market. This drug beat the odds. It demonstrated non-inferiority to piperacillin/ tazobactam in clinical trials, Merck declared ‘steadfast commitment to meeting the needs of the health care community’. Despite this, it was discontinued.

Why is this happening in an area of need? Beyond the fact that the market is weak and better pull incentives are required, one factor is that we are not defining the value of novel antibiotics effectively. The clinical trial endpoints are designed to demonstrate clinical non-inferiority due to ethical obligations of withholding treatment, but drugs like Recarbio deliver far more value to society than purely their clinical benefit. They are a required tool for us to combat the rise of AMR (particularly for a product with 3 of the major gram-negative indications of HABP/VABP, cUTI and complicated intra-abdominal infection). There is room to better consider value from a market access perspective earlier in clinical evidence generation plans. 

What antibiotic development can learn from HIV

This valuation gap strikes me. I see parallels in the way HIV drug development has closed a different kind of gap: the successful engagement of the HIV community in HIV prevention. Drug developers understood that in order to ensure people take PrEP effectively, PrEP needs to meet them where they are. People need access to a choice of prevention methods to suit their lifestyle. Community Advisory Boards (CABs) are now consulted regularly by drug developers (Gilead, ViiV) and Good Participatory Practice (GPP) is published and sets standards to engage a broad range of stakeholders across the whole trial lifecycle. This is now the norm. It is important to acknowledge these mechanisms did not arise spontaneously, rather they were largely due to failed trials that did not meet community needs and vocal and effective community advocates demanding their representation. However, as a result, novel formulations are developed and broader demographics are included in trials to meet direct community needs. 

For example, after consistent input at community meetings, Gilead included pregnant and lactating people in its Phase 3 PURPOSE 1 trial. This was the first Phase 3 HIV prevention trial to include this population, a key step to meet the urgent unmet need. And now, WHO guidelines confirm lenacapavir use in and guidance for pregnancy and breastfeeding. Gilead confirms ‘our conversations with stakeholders were of immeasurable value in shaping the design of PURPOSE 1.’ 

What strikes me here is how consultation of the HIV community became the norm in clinical trial design. The biggest drug developers do it regularly, and if they don’t, it looks like they are out of touch with the true needs in HIV care and are seen to be practicing ‘old’ ways of working. ViiV Healthcare regards community engagement as ‘instrumental to the success of HIV innovation’. 

Plan evidence for access from the outset

Involving payers and market access experts before evidence plans are finalised may help identify gaps relevant to reimbursement and access. We know these drugs are needed. And we know in order to keep the drug developers in the game these antibiotics need to be valued appropriately. Approaching market access experts as key partners in trial design could also give investors confidence in the robustness of data produced. Better data means stronger demonstration of value, more successful launches and wider access to products. This success will keep drug developers in the game. Let’s better engage our market access experts, demonstrate the value of antibiotics, and ensure we don’t keep losing successful clinical solutions due to ‘portfolio reviews’.

Make early engagement standard practice

I am proposing that partners across the AMR ecosystem advocate for and enable better valuation of early stage assets. The mechanism remains open to discussion but could look like:

• Adopting an antibiotic-specific GPP 

• Creating local market access advisory committees who partner SMEs to pressure test evidence generation plans prior to trial start 

• Making clinical teams accountable for involving access experts during protocol development

The value of this early engagement can then be assessed through the resulting changes in clinical evidence design and if they are enablers of better/ faster/ broader access decisions.

What do you think? Get in touch with us, I’d love to discuss further.

Note: I recently joined the ARMoR team. My background is in the pharmaceutical industry and I spent the last two years focused on HIV treatment and prevention. I am seeing parallels between HIV and AMR and am a strong believer in open collaboration and information sharing across disciplines to address challenges more efficiently.

AMR = antimicrobial resistance; HABP/VABP = Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia; cUTI = complicated urinary tract infection; SME = Small and medium-sized enterprise biotechs