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In the News: April 2021 Regulatory and Development Updates

Each month, Camargo’s “In the News” series highlights important changes and advancements in the regulatory and development space and explores how those changes could impact your program.

FDA’s Accelerated Approval Program Comes Under Fire

The public’s faith in drugs approved under the FDA’s accelerated approval program is not blind — it relies heavily on the industry’s follow-through on confirmatory trials and the FDA’s subsequent review and final approval. Yet many, including the FDA’s top oncology drug reviewers, have found that the Agency has not taken action to remove products from the market or withdraw indications when these confirmatory trials have failed to show benefit. A recent meeting of the Oncologic Drugs Advisory Committee (ODAC) to review these drugs without confirmatory benefit, however, revealed that committee members were unwilling to remove the indications. It will be interesting to see if the FDA follows the ODAC recommendations.

The meeting was prompted by a publication by Richard Pazdur, M.D., head of the FDA’s Oncology Center of Excellence, and Julia Beaver, M.D., the Center’s chief of medical oncology, In it, they laid out their analysis of accelerated approvals for 35 oncology indications for anti-programmed death ligand 1 antibodies and reported that for 10 of the 35 indications, the confirmatory trials failed to show a benefit.

The members of the ODAC voted to continue the use of four of the six drugs it discussed during the meeting, despite failed clinical trials.

Drug Product Indication Committee Vote on Whether to Maintain Approval
Tecentriq Triple-negative breast cancer 7 Yes, 2 No
Keyturda First-line bladder cancer 5 Yes, 3 No
Tecentriq First-line bladder cancer 10 Yes, 1 No
Keytruda Third-line stomach cancer 2 Yes, 6 No
Keytruda Second-line liver cancer 8 Yes, 0 No
Opdivo Second-line liver cancer 4 Yes, 5 No


These votes likely stem from the members’ belief that withdrawing the indications would leave patients with no options and that some patients are on the tails of the clinical response curves.

Often there is a tail of the curve, and it would be terribly devastating for a patient to not receive the therapy, recognizing there are access programs with disparities of healthcare and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get that.
— Committee member Diane Reidy-Lagunes, MD, commenting on her vote to support the continued approval of KEYTRUDA’s (pembrolizumab) indication in gastric cancer

Despite Dr. Reidy-Lagunes’s concerns, the ODAC voted 6-2 to withdraw the indication from pembrolizumab, reflecting a collective judgement that patients have other approved options. In contrast, in the cases of the four drugs for which the ODAC voted to maintain approval, there was widespread consensus that the patients had few options, if any, and that continued clinical trials would not alter their view.

My main concern is that none of the pending studies, as best I could tell, would definitively answer the question of either monotherapy or the position in terms of lines of therapeutic sequencing for this agent.
—Panelist Mark Lewis, M.D., referring to additional proposed studies of KEYTRUDA in gastric/gastroesophageal junction cancer

It is unknown what the FDA response to this ODAC meeting will be. Some observers were surprised the FDA even held the meeting, suggesting that the FDA could have acted without it. We recently reported that the FDA is proposing to withdraw Makena (hydroxyprogesterone caproate), approved in 2011 using the same accelerated approval pathway as the oncologic drugs discussed above. Proponents of Makena make similar arguments that the confirmatory clinical trial results are not relevant to actual use and that withdrawal will leave patients and their babies without any approved option.

FDA Signaling Future Civil Money Penalties for Violations

The requirements of often come as a surprise to those unfamiliar with the particulars of drug development. Regulatory requirements obligate the party responsible for an “applicable clinical trial” to 1) register the trial and 2) report the trial results to the database. Since the information on is publicly available, these requirements are often a source of consternation for sponsors, who are required to attest to their conformance with the requirements by submitting FDA Form 3674 with certain IND and NDA submissions.

Section 301(jj) of the FD&C Act allows for significant monetary penalties for failure to fulfill the obligations described above. However, in the 10 years since the establishment of the Clinical database, the FDA has shown little if any enthusiasm for enforcing the requirement, to the extent that some sponsors Camargo has spoken with have been reluctant to fulfill the requirements.

This may be changing. In April, the FDA issued a Notice of Noncompliance to Acceleron Pharma, Inc., threatening an administrative action seeking civil money penalties for its failure to comply with the requirements. The penalty can be up to $10,000 per day until the violation is corrected. That kind of penalty can put a substantial and difficult-to-explain dent in a sponsor’s budget.

FDA Issues Final Guidances on Issues Arising from COVID-19

The FDA issued two guidances in April related to problems and questions connected to application approvals during the COVID-19 pandemic. Both were issued as “Final,” or without the opportunity for public comment, and addressed the current public health emergency.

Where Are Our Virtual Inspections?

Timely FDA inspections were an early casualty of the COVID-19 pandemic, along with timely application approvals. Relatively early, the FDA hinted that alternative methods, including “virtual inspections” might be available to mitigate the problem. Some sponsors aggressively pursued this option after receiving a CRL because of a delay for a required inspection. Almost universally, requests for remote inspections were rebuffed by the FDA, and the FDA’s growing backlog of inspections has subsequently received scrutiny from several sources. Possibly in response, the Agency has issued the guidance Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency.

The title of the guidance is worth noting—“Remote Interactive Evaluations,” not “Inspections.” Indeed, from the guidance:

FDA may request to conduct a remote interactive evaluation prior to or following other types of regulatory oversight activities (e.g., an inspection or a request for records or other information). (emphasis added)

This is further clarified in a footnote:

A remote interactive evaluation is not the same as an inspection as described in section 704(a)(1) of the FD&C Act or a request for records or other information in advance of or in lieu of an inspection, as described in section 704(a)(4) of the FD&C Act. Similarly, a remote interactive evaluation or a request under section 704(a)(4) does not constitute an inspection for purposes of section 510(h)(3) of the FD&C Act.

Given that, what is the point? Per the guidance,

FDA has developed this guidance to describe various remote interactive tools we may request to use to conduct an evaluation. In this guidance, we refer to our use of any combination of these interactive tools as a remote interactive evaluation.

The guidance goes on to generally describes the tools and the mechanics of using the tools for programs, including (but not limited to) Pre-Approval Inspections (PAIs), Pre-License Inspections (PLIs), Post-Approval Inspections (PoAIs), Surveillance Inspections, Follow-Up and Compliance Inspections, and Bioresearch Monitoring (BIMO) Inspections.

So, we are perhaps a step closer to remote inspections, but not there yet.

How Can I Get my ANDA Program Back on Track?

The pandemic has caused numerous complications for ANDA sponsors, primarily in the form of delays to their development programs and to reviews of their applications. Since these problems have generated many questions for the FDA, the Agency has attempted in a recent guidance to summarize the most frequently encountered and important issues in a question-and-answer format.

The guidance, Development of Abbreviated New Drug Applications During the COVID-19 Pandemic – Questions and Answers, presents questions and answers in the following categories: a) generic drug product development, b) submission and assessment of ANDAs, and c) marketing and exclusivity. The questions and answers deal, primarily and unsurprisingly, with issues which arise because of delays caused by COVID-19, such as expiring drug batches used in BE studies, delays in the BE studies themselves, how tentative approval figures in, and the potential impact on 180-day exclusivity.

Since the current approval process is somewhat of a moving target, Camargo can assist you in adjusting your development program according to the FDA’s evolving thinking as we move through the pandemic and beyond.


Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President, Regulatory Operations