Zelboraf/Clinical Trial Length | Diaceutics

Zelboraf/Clinical Trial Length


This case shows how Rx/Dx co-development can enable faster regulatory approval and a shorter and cheaper clinical trial program. It highlights the particular features and success factors that enabled Roche to use a targeted strategy to streamline the Zelboraf clinical trial program. It will help you understand:
  • How Roche, by targeting Zelboraf through the BRAF biomarker, was able to obtain regulatory approval with a considerably shorter and cheaper clinical trial program, thereby fulfilling one of the original personalized medicine promises to pharma
  • The particular features and success factors that enabled Roche to use such a targeted strategy to streamline the Zelboraf clinical trial program
  • How this approach by Roche has resulted in BRAF mutation testing being embraced, despite initial reimbursement issues

1: Case Summary

This case will help you understand:

How Roche, by targeting Zelboraf through the BRAF biomarker, was able to obtain regulatory approval with a considerably shorter and cheaper clinical trial program, thereby fulfilling one of the original personalized medicine promises to pharma.

The particular features and success factors that enabled Roche to use such a targeted strategy to streamline the Zelboraf clinical trial program.

How this approach by Roche has resulted in BRAF mutation testing being embraced, despite initial reimbursement issues.
Key messages:

Roche managed to speed up clinical development and regulatory approval by leveraging a set of success factors that may guide future targeted therapy commercialization strategies.

Use well-known biomarker over a novel one when possible.

Establish early partnership with diagnostic companies.

Only study safety in the target population.
Key actions:

Understand how diagnostics can streamline therapy clinical trials.

Start the regulatory dialogue early to establish potential hurdles and opportunities.

2: Melanoma Treatment Zelboraf Approved in Parallel with Cobas 4800 BRAF V600 Mutation Test

INDICATIONS AND USAGE

ZELBORAF™ is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. (1, 5.10)
Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. (5.10, 14).



INDICATIONS AND USAGE

The cobas® 4800 BRAF V600 Mutation Test is an in vitro diagnostic device intended for the qualitative detection of the BRAF V600E mutation in DNA extracted from formalin-fixed, paraffin-embedded human melanoma tissue. The cobas® 4800 BRAF V600 Mutation Test is a real-time PCR test on the cobas 4800 system, and is intended to be used as an aid in selecting melanoma patients whose tumors carry the BRAF V600E mutation for treatment with vemurafenib.

So What?

Both drug and test were developed by Roche using their two health care arms in therapeutics and diagnostics. For the first time, the drug label indicated a testing requirement.

As was the case with Herceptin/HercepTest, both Zelboraf and BRAF were approved on the same day.

3: The Prospect of Shorter, Cheaper Clinical Trials is One of the Original Promises of Personalized Medicine

 
 
Focusing clinical trials on targeted subpopulations would slash their size, duration and cost.
 
So What?

In theory, targeted therapy clinical trials could be shorter and cheaper as the therapy would demonstrate a higher efficacy or safety profile in the stratified group.

4: Personalized Medicine Promises Hampered Until Now by Lack of Regulatory Flexibility and Incentives

 
 
Future regulatory guidance requiring a demonstration of safety in biomarker-negative as well as biomarker-positive subpopulations would further reduce potential savings in cost and time and might increase cost and duration of trials in comparison to an all-comers approach.
So What?

In practice, delivering on this promise has been difficult due to regulatory requirements to include non-targeted populations in safety studies and late identification of biomarkers in the clinical program.

5: Zelboraf's Clinical Program was Much Shorter than Usual for Similar Therapies

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So What?

Clinical trial length, as well as approval time for Zelboraf after the application to the FDA, was significantly shorter than the average for comparable oncology therapies.

Several factors were involved in allowing this timeline.

6: Success Factor 1: FDA is More Amenable to Faster Approvals for High Mortality, Under-Treated Diseases

So What?

Metastatic melanoma has a poor prognosis and is a difficult-to-treat condition. Given the few options for these patients, the FDA is more likely to grant a quick approval.

Commentary

Whereas melanoma is generally diagnosed in its early stages, it is the deadliest and most aggressive form of skin cancer when it spreads to other parts of the body. A person with metastatic melanoma typically has an average life expectancy measured in months. Only around one in four people with metastatic melanoma are expected to be alive one year after their diagnosis.

The one year survival rate for people with metastatic melanoma in one organ is 36 per cent. For those with the cancer in two organs it is 13 per cent. In those with Stage 4 melanoma in three or more organs, it is 1 per cent.

7: Success Factor 2: Safety Evaluation in Biomarker-Negative Populations Not Required for Zelboraf

So What?
The Zelboraf clinical trials used the enrichment trial design, so it was safety tested only in BRAF mutation positive patients.
Commentary
With this enrichment trial design, all patients are tested by means of a CDx assay, but only the CDx positive patients are enrolled in the study and subsequently randomized to either the new targeted drug or to the standard treatment. This means that Zelboraf was safety tested only in BRAF mutation positive patients, while most other drugs are required to establish proof of safety in responders and non-responders.

Such trial design significantly lowers the patient numbers required for a registration trial, a point that is especially significant for indications with already low patient populations.

Another advantage of this design is that it generally requires a smaller number of patients to be randomized compared with the traditional design, due to the fact that only patients who have a BRAF mutation positive status are enrolled, thus making the study population more homogeneous.

Confirmation of BRAF V600E mutation using an FDA-approved test is required for the selection of patients appropriate for Zelboraf therapy. The efficacy and safety of Zelboraf have not been studied in patients with wild-type BRAF melanoma.

8: Success Factor 3: BRAF Marker is Already Established in Clinical Literature and a BRAF Test is Commercially Available

So What?

BRAF testing has been available for some time from a range of US laboratories due to applications in a number of oncology areas. One key aspect of the FDA premarket approval process is the quality of testing done in clinical practice (beyond the highly structured clinical trials). Due to the long use of BRAF testing in the US, the lab-to-lab variability of the testing was known.

9: Success Factor 4: Early Partnership Between Rx (Roche Pharma) and Dx (Roche Molecular Systems)

 
 
Even under these assumptions, the economics for the diagnostics were not compelling compared to those for the therapeutics examined, averaging only 2-4% of eNPV on an onocology therapeutic. In fact, making less favourable assumptions results in negative eNPVs for the diagnostic.

So What?

Many Rx-Dx collaborations undervalue the Dx role.

Roche, however, may easily value the overall revenue potential of the targeted therapy. The earlier the partnership is established, the more experience in the clinical trials with the commercial test is gained, and this is experience the FDA values in its approval processes.

10: Zelboraf has been Steadily Adopted as a Personalized Treatment

 
 
Oncologists have embraced BRAF mutation testing; slightly more than one-quarter said they face barriers and challenges with screening. A lack of reimbursement is the most challenging issue for BRAF mutation testing....commercial plans (88%) and Medicare Advantage plans (68%) are expected to cover it within the next 12 months, from a U.S. Physician & Payer Forum report entitled Dramatic Changes in the Malignant Melanoma Landscape: How Will U.S. Payers and Prescribers Limit or Promote Market Access for Recently Launched and Emerging Brands?
FierceHealthcare, April 2012
So What?

BRAF mutation testing required for the use of Zelboraf has been embraced by oncologists since its launch in 2011.

Although reimbursement issues have initially been challenging these are expected to be covered within the next 12 months [by 2013].

11: Key Messages

Key messages:

Roche managed to speed up clinical development and regulatory approval by leveraging a set of success factors that may guide future targeted therapy commercialization strategies.

Use well-known biomarker before therapy.

Establish early partnership with diagnostic companies.

Only study safety in a target population.
Key actions:

Understand how diagnostics can streamline the therapy clinical trials.

Start regulatory dialogue early to establish the potential hurdles and opportunities.

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