The Role of the Oncology Drug Advisory Committee (ODAC) in FDA Review

Introduction: In April 2021, the U.
S.
FDA held a 3-day ODAC (Oncologic Drugs Advisory Committee, ODAC) meeting, which focused on the role of PD-1/PD-L1 inhibitors in urothelial cancer (UC) clinical trials.
controversial issue
.

After the meeting, some sponsors voluntarily withdrew accelerated approval (AA) indications

introduction:

Picture from: US FDA official website

AC and ODAC

AC and ODAC

Organizational Structure and Main Responsibilities

Organizational Structure and Main Responsibilities

There are many disciplines involved in drug regulation, and with the acceleration of information updates, the regulatory authorities will also appear powerless
.

At this time, the Advisory Committees (AC) came into being and played an important role in drug regulation

Picture from: US FDA official website

Currently, the FDA has a total of 31 ACs, managed by centers for human drugs, medical devices, and pediatrics, to further support FDA's mission to protect and promote public health
.

The human drug advisory committees (human drug advisory committees) include 18 ACs, such as: endocrine and metabolic drugs AC, cardiovascular and renal drugs AC, peripheral and central nervous drugs AC, etc.

Picture from: US FDA official website

Each AC is generally composed of a chairman and several members (mostly 10 to 15 people) to ensure that their interests are "relatively balanced", including a consumer representative, an industry representative and a Patient representatives (on demand), FDA can also add experts in related fields according to the needs of the product, generally AC is updated every 2 years
.

AC members make objective and fair evaluations on the issues discussed within the scope of their own knowledge
.

Industry representatives address various issues of concern to the industry, but they do not represent employers, but express their views and views on the issue

Consumer representatives are technical experts with specific relationships with consumer protection organizations who represent the interests of consumers and may also be potential audiences for new products
.

Patient representatives usually need to have a general knowledge of the relevant disease, understand relevant professional materials and data, and they can also provide opinions on new products through their own experience [2]

As far as ODAC is specified, it consists of 13 core members with voting rights, including the chairman
.

Members are selected from leading authorities in Introduction to Oncology, Pediatric Oncology, Hematology Oncology, Immuno-Oncology, Biostatistics, and other related specialties

FDA to 'Fully Adopt' AC's Recommendations

FDA to 'Fully Adopt' AC's Recommendations

But AC's advice is not legally binding

But AC's advice is not legally binding

It should be noted that the FDA will adopt the AC's opinions when making decisions
.

Moreover, some provisions of the FDA's 2007 Amendment Act pointed out that AC's recommendations will affect the approval process of new drugs, and in fact the two sides often agree

In a study that analyzed 376 FDA AC votes from 2008 to 2015, there were 83 (22%) disagreements between AC recommendations and FDA decisions
.

Of these 83 inconsistencies, FDA was more conservative than AC in 62 (75%) and AC was more conservative in 21 (25%)

In August 2020, a retrospective study analyzed the reasons behind the inconsistency between ODAC recommendations and FDA decisions, and compiled the ODAC meeting minutes published on the FDA's official website from 2009 to 2019.
A total of 6 examples were selected.
The tumor products involved include: : selinexor, panobinostat, olaparib (olaparib), hexaminolevulinate hydrochloride, erlotinib (erlotinib) and peginterferon alfa-2b [3]
.
Let's take erlotinib (Tarceva) as an example to see where ODAC and FDA disagree
.

The SATURN study on erlotinib

The SATURN study on erlotinib

Soul torture by ODAC

Soul torture by ODAC

Erlotinib is an oral EGFR inhibitor developed by OSI Pharmaceuticals and Genentech (Roche)
.
The indication, submitted in 2009, is first-line maintenance monotherapy in patients with locally advanced or metastatic NSCLC who have not progressed (including stable disease) after first-line platinum-based chemotherapy
.
The application for the indication is based on the SATURN study [4], a global, randomized, placebo-controlled trial, investigating the FDA's Special Protocol Assessment (SPA) mechanism
.

The SATURN study included 889 patients with stage IIIb/IV NSCLC who had not progressed after first-line platinum-based chemotherapy and were randomized to receive erlotinib or placebo
.
It is important to start erlotinib maintenance therapy immediately after chemotherapy ends, rather than waiting until disease progression
.
The primary endpoint of the study was PFS in the total and intention-to-treat (ITT) populations, as well as PFS in EGFR-positive patients
.
Secondary endpoints were OS in the ITT population and EGFR-positive patients, and PFS and OS in EGFR-negative patients
.

The study achieved the primary endpoint, with HR=0.
71 (P<0.
0001) for PFS value in the erlotinib group in the ITT population, and HR=0.
69 (P<0.
0001) in the EGFR-positive group
.
The study also met secondary endpoints, with HR = 0.
81 (P = 0.
0088) for OS in the erlotinib group in the ITT population and HR = 0.
77 (P = 0.
0063) in EGFR-positive patients; however, in EGFR-negative patients, PFS and OS did not reach statistical significance
.

Figure: OS values ​​in the erlotinib group and EGFR-positive patients in the ITT population of the SATURN study
.
Image from: Lancet Oncol.
2010; 11(6): 521-9.

There are two main issues discussed at the ODAC meeting [5] (held in December 2009): 1.
The study design cannot prove that starting erlotinib immediately after first-line chemotherapy is better than starting erlotinib after progression
.
2.
The results of the study showed that the OS improvement in the maintenance treatment group was not significant
.
The voting results of ODAC were: 1 vote in favor and 12 votes against
.

The FDA summarizes the 6 main issues raised by ODAC [5]: 1.
OS is the endpoint for evaluating clinical benefit, not PFS
.
2.
The patients who have progressed after chemotherapy (as the control group) are given corresponding maintenance therapy drugs, which can prove that maintenance therapy is better than delayed therapy (only a small number of patients in the control group received EGFR-TKI therapy after disease progression in the study).
)
.
3.
The OS benefit of important subgroups (EGFR-negative patients and squamous cell carcinoma patients) is unclear
.
4.
The OS results in EGFR-positive patients were disappointing (large differences) compared with PFS
.
5.
Consider other treatment options, use pemetrexed maintenance therapy, or use erlotinib, docetaxel, pemetrexed monotherapy after disease progression, the efficacy may be better than erlotinib maintenance therapy
.
6.
Quality control of EGFR immunohistochemistry (IHC) kits and EGFR mutation kits, the former may have different results, and the latter has not been approved by the FDA
.

Let's look at the consideration of the affirmative vote in ODAC [5]: 1.
In terms of clinical endpoints: FDA and the applicant have fully communicated about the trial design
.
The final trial met the endpoints that were pre-specified by the sponsor and deemed reasonable by the FDA
.
The FDA and the applicant have discussed the issue of OS endpoints, but the applicant considers that subsequent treatment results may have confounding effects, so it continues to choose PFS as the primary endpoint
.
2.
In terms of clinical evaluation: Before drug maintenance treatment, clinicians will carefully evaluate the patient to avoid unreasonable treatment
.
Approval of a reasonable maintenance regimen during stable disease does not harm the patient
.

Erlotinib was approved by the FDA on April 16, 2010, despite objections from the ODAC
.
Notably, this was approved 13 months after the application was submitted, and the wording of the approval did not include the applicant's desired "first-line" qualification
.
Importantly, the SATURN study is a post-approval commitment for the accelerated approval (AA) of the erlotinib New Drug Application (NDA)
.
Although the FDA approved this indication, it was accompanied by another post-marketing commitment to conduct an additional NSCLC randomized controlled trial comparing erlotinib maintenance therapy with post-progression therapy , and the primary endpoint was OS, to answer previously questioned questions
.

ODAC is an important aid for FDA to ensure science and fairness

ODAC is an important aid for FDA to ensure science and fairness

Inconsistencies between ODAC and FDA are rare
.
Overall, when ODACs are conservative, the value of a drug's new mechanism of action, new treatment options for patients, and regulatory precedent may be important factors influencing FDA's decision-making
.
In such cases, FDA will typically require the applicant to submit additional data that will influence FDA's final decision
.
Treatment options that ODAC "opposes" but are still approved are often drugs with new mechanisms of action that offer treatment options for refractory patients
.
Therefore, it is very important for applicants to identify patient groups with unmet therapeutic needs [3]
.

When the FDA is more conservative, it may give more consideration to the design of clinical trials, trial endpoints, and data integrity
.
Consistent with FDA's goal of maintaining patient safety, drug toxicity is an important factor in the outcome of the ODAC discussion and an important factor in the FDA's final decision
.
Based on ODAC discussions, the FDA can better understand complex treatment issues and make regulatory decisions
.
With the rapid development of tumor treatment modalities and clinical trial designs, this model has become increasingly important [3]
.

references

1.
https:// FDA's management of drug expert advisory committee and its enlightenment to my country.
China Pharmaceutical Affairs.
2009; 23(3): 303-306.

3.
Ther Innov Regul Sci.
2021; 55(1): 98-110.

4.
Lancet Oncol.
2010; 11(6): 521-9.

5.
US Food and Drug Administration (FDA).
Transcript for the December 16, 2009 Meeting of the Oncologic Drugs Advisory Committee (ODAC).
2009b