Trial outcomes and value – Explaining contemporary clinical trial issues
Summary:
For recently approved drugs with premium prices, healthcare budgets are being stretched and are likely to be rationed in one form or another. To justify the value of the drug, companies have to invest more on measuring their drug’s benefit or outcomes. For companies developing one-off treatments such as gene and cellular therapies, there are expectations that a single price per treatment course will capture the value of a lifetime cure. Here we explore how some clinical trials are now measuring outcomes and endpoints for both small molecules and innovative therapies.
How does a clinical trial translate into value?
Until recently, a positive well-controlled Phase III programme conducted in a large number of patients would usually lead to commercial success, despite the patent position. These days, a positive clinical trial is far from guaranteed to translate into commercial success in many indications and drug sponsors are having to do things differently to demonstrate value to payers. This is even more acute as cheap generic drugs comprise the standard of care in many indications and the unmet medical needs are in smaller, higher value, more difficult to treat patient populations.Innovative therapies mean innovative pricing
The approval of drugs with very high prices and innovative cell and gene therapies that are proposed to be priced as millions of dollars per treatment magnify this issue of demonstrating value. Innovative therapies are giving rise to innovative pricing mechanisms that invariably involve measuring to demonstrate value. This is easier said than done. Likely winners- Clinical research organisations (CROs) such as Parexel, IQVIA and ICON, which have added long-term outcome studies to their product offerings.
- Pharma and biotech companies that able to provide positive outcome data.
- Payers, which have to sit back and wait for outcome data before reimbursing.
- Patients, who are more likely to receive drugs that provide them a benefit.
- Pharma and biotech companies that cannot show positive outcomes.
- Whoever collects the data: if small pharma and biotech companies have to collect outcomes data and follow patients in registries to be reimbursed, their costs will go up.
Clinical trials, outcomes, value and pricing
Clinical trial definitions: Endpoints and outcomes
The announcement of clinical trial results by biotech and pharma companies is frequently associated with sometimes extreme share price volatility if success or failure is unexpected. When AstraZeneca reported the long-anticipated clinical trial result for its checkpoint inhibitor Imfinzi in first-line lung cancer, which failed to improve overall survival, the company lost $14bn from its market capitalisation. Therefore, the determination of success or failure is initially made by the market when investors interpret the primary and secondary endpoints of the study. There is significant debate on whether the meeting of a primary endpoint to an accepted level of statistical significance in an overpowered study (one that enrols many hundreds of patients to measure a small effect) is clinically or commercially significant. So, starting with mainstream indications and drugs for diabetes, for example, we will first define what an endpoint is, and explain how it differs from the more robust outcome, then discuss how outcomes are more likely to result in commercial success. Endpoints are numerical evaluations of an effect of a drug or device on a clinical trial population. For a study to be successful, the active arm must be more efficacious in the primary endpoint measurement than the placebo arm by a sufficient margin to be statistically significant (ie a low probability the result occurred by chance). When this occurs, the primary efficacy endpoint can be said to have been met. An example of a pragmatic, hard clinical endpoint is overall survival (OS) after five years in a cancer clinical trial. It is easy to measure and the value of returning a patient to the workforce is considerable. But measuring this particular endpoint can take much longer than five years because not all patients are enrolled at the same time and, as a result, the cost of the study is very high. Endpoints that are related to OS, such as progression-free survival, are often used to achieve regulatory approval more quickly than if OS had been the primary endpoint. Although all this is logical, clinical trial endpoints in many other non-oncology disease indications are much less pragmatic and are linked to, or are only indicative of, hard clinical effectiveness endpoints. These are called surrogate endpoints and are part of an emerging issue that links innovative therapies and value.Surrogate endpoints
In diabetes patients, for example, a primary surrogate endpoint (on which the success of a trial is judged) is almost always a reduction in either fasting plasma glucose (FPG) or glycosylated haemoglobin (Hb1Ac) and their maintenance below a target level more associated with that seen in non-diabetic patients. This endpoint is almost always measured against a matched and randomised group of patients that receive a placebo and the study sponsor’s goal is that this arm does not show the significant reductions in FPG or Hb1Ac that are observed in the active arm of the study. Although well accepted by the FDA for the purposes of approving anti-diabetic drugs, the surrogate endpoints of FPG and Hb1Ac only imply a clinical benefit rather than actually measuring a more tangible clinical effect of (what would be the failure of) anti-diabetic medicines, such as lower limb amputation, blindness or death. Surrogate endpoints such as these are used to approve anti-diabetic drugs because the time, cost and ethics of running a study to measure these tangible health outcomes have been too great or unacceptable for patients in the placebo arm. Even the measurement of intermediate outcomes of diabetes such as proteinuria, retinopathy or foot ulcers may be unethical because it would result in some deterioration in the health of the patients (particularly in the placebo group) during the study and may not be easily reversed. This is unless the placebo arm patients are treated with the existing standard of care and the active arm seeks to lower the rate of these intermediate or even final outcomes.Primary endpoints
The primary endpoint (whether surrogate or clinical) is usually the key measure of a clinical trial that might, if achieved, result in the regulatory approval of the drug, although this may not lead to commercial success. The drug sponsor’s choice of primary endpoint should be one that is widely accepted as a validated measure of clinical efficacy and that choice should hopefully be discussed and agreed with the regulators before the study starts (a prospectively-defined primary endpoint). Unfortunately, unless the FDA agrees it in a special protocol assessment (SPA) or its equivalent with the European Medicines Agency (EMA) prior to the commencement of the clinical study, there is usually no commitment for a regulator to approve a drug on the basis of a drug sponsor’s choice of primary endpoint. In some cases, even when an SPA has been agreed, changes to the study or the standard of care may have invalidated it. Some hypothetical examples of met and missed endpoints and their impact on the approvability of a drug are illustrated in Exhibit 1. In the case of diabetes, for example, secondary endpoints can be the reduction in the amount of insulin used when testing oral anti-diabetic drugs or the patients’ weight gain, and are useful supportive measures of the drug’s value. Estimated approvability based on clinical trial results:Reported results | Drug #1 | Drug #2 | Drug #3 | Drug #4 | Drug #5 |
Primary efficacy endpoint | Met | Met | Missed | Missed | Missed |
Secondary efficacy endpoints | Met | Most met | Some met | Most missed | Most missed |
Safety endpoints | ~placebo | Worse than placebo | ~placebo | ~placebo | Worse than placebo |
Retrospective endpoint analysis | No | No | No | Yes | No |
Retrospective subgroup analysis | No | No | No | No | Yes |
Comment on approval | Ideal result | Almost ideal | Difficult | Unlikely | Highly unlikely |
The moving goalposts in endpoints and value
The five branded anti-diabetic drugs with positive outcome studies:
Companies | Name | Brand Name |
Eli Lilly | Empagliflozin | Jardiance |
Johnson & Johnson | Canagliflozin | Invokana |
Novo Nordisk | Liraglutide | Victoza |
Novo Nordisk | Semaglutide | Ozempic |
Astra Zeneca | Dapagliflozin | Farxiga |
Outcomes-based pricing comes to new drugs
Innovative medicines bring new challenges
Gene therapy companies:
Companies | Acquisition Price ($bn) | Price Close ($) |
Kite | 11.9 | – |
Juno | 9.06 | – |
Spark Therapeutics | 4.8 | – |
Nightstar Therapeutics | 0.85 | 25.33 |
Orchard Therapeutics | 1.6 | 18.33 |
The impact of pricing issues for innovative therapies
Where there’s a will, there will be a way
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