Lyman BioPharma Consulting LLC

Advice and Resources for the Biotech Industry

Advice and Resources for the Biotech Industry

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Not Accepting the Outcome When the (FDA) Vote Doesn’t Go Your Way

Donald Trump’s recent pronouncement that he would not necessarily accept the results of the presidential election elicited an avalanche of angst across America. Such a move would threaten the very pillars of democracy that have been in effect for some 240 years. While Trump and his supporters will undoubtedly have feelings of disappointment, disillusionment, and anger if he loses (which is looking increasingly likely), challenging the outcome itself would be unprecedented. What would Donald Trump do if he were CEO of a biopharma company that had its drug rejected by the FDA?

It’s a painful thought to consider. Would he challenge the outcome, or simply file an appeal? Might he suggest the FDA be scrapped, or threaten to sue it? Maybe he’d take his drug to Europe or Asia and hope to win approval there? No doubt no matter what path he would take, we’d be hearing how the drug approval process was rigged against him, and how corrupt the system is. Thankfully, Trump’s business path has not taken him into the realm of biopharma.

The management, staff, and supporters of biopharma companies certainly share these same feelings of discontent when they see their experimental drugs' bright prospects dashed by negative votes from an FDA advisory committee, or the FDA itself. In many cases the company will infer that the FDA erred in its decision making because they somehow didn’t understand the application. What can a company do if this happens? Different companies have taken distinct paths. Let’s look at a few examples.

Accept the Results and Walk Away
One approach is to simply accept the FDAs rejection, admitting that the data wasn’t up to snuff, and walk away. Many companies are loath to take this approach because to do so looks bad to shareholders. How often does a company want to publicly admit it screwed up? Stock prices generally plummet following the rejection of a drug. Amgen recently confounded both its shareholders and the analysts who follow the company by not saying a word about the rejection of its drug etelcalcitide (Parsabiv). Maybe it’s hoping that some good news is on the near-term horizon that can serve to distract shareholders from the problem?

Appeal, Appeal, and (If Necessary) Appeal Again
A more common strategy is to meet with the FDA in hopes of resolving the issues that led to rejection. This meeting strategy is one being pursued by many companies. Examples include Chiasma’s acromegaly drug Mycapssa, whose CEO, Mark Leuchtenberger, said after its drug was rejected in April 2016, “we continue to respectfully disagree with the FDA’s decision, and we continue to believe that our NDA, as filed, demonstrates the efficacy and safety of Mycapssa.”The company has asked for additional meetings with the agency, but the CEO was already hinting at what will happen next, “If the outcome is not acceptable to us, we may pursue dispute resolution with the agency.” Bill Lis, CEO of Portola, had this to say when the FDA rejected his company’s application for AndrexXa, “Portola’s goal is to define the most expedient path to approval so we can meet the needs of these patients who have no alternative. We plan to meet with the FDA as soon as possible.” PTC Therapeutics also vowed to undertake “multiple cycles of appeals” following the FDA’s denial of its application for its Duchenne muscular dystrophy drug Translarna. Finally, Adamis Pharmaceuticals had its application for approval of their epinephrine injection product rejected not just once, but twice, by the FDA. Dr. Dennis J. Carlo, President and CEO of Adamis, commented, “We look forward to working with the FDA to resolve the remaining issues.”

Get Patients and the Public Involved
There are two recent examples of drugs that didn’t really measure up very well in their clinical trials, but wound up being approved anyway. In both cases it was public involvement that wound up carrying the drugs over the approval threshold. One was Sprout Pharmaceutical’s flibanserin (marketed as Addyi), its drug to stimulate female arousal. The FDA twice rejected the drug for overall ineffectiveness (in 2010 and in 2013). The company launched an online campaign “Even the Score” with consumer advocacy groups pushing the FDA for approval. The main theme was that it was time for women to get help in an area for which the agency had previously approved a large number of drugs for erectile dysfunction in men. Despite concerns over side effects and only a modest (but demonstrable) effect, the FDA approved the drug in June 2015.

A more recent example of a drug that didn’t get the votes it wanted from an FDA advisory panel is Sarepta’s Duchenne muscular dystrophy drug Eteplirsen (Exondys 51). In 2015 the FDA initially
declined to approve the drug (which was tested on only 12 boys) because it, “showed no clear benefit after 24 weeks in prespecified clinical end points, such as changes in a 6-minute walk test. Those trials also suggested the possibility of safety problems, including renal toxic effects and thrombocytopenia.”

The drug went before an FDA advisory committee meeting in April 2016. This hearing had more than 1,000 attendees, including patients and their families, doctors, scientists, and legislators. Seven members of the advisory panel did not find the drug to be clinically effective, three members were in favor of its approval, and there were 3 abstentions. Pressure on the agency from patients and their families was enormous. The FDA decided to approve the drug, with the proviso that a larger trial needed to be done to establish that the drug really was of benefit to patients. Sarepta did not need to wait to get the new clinical results before selling the drug, which it priced at $300,000 per year. However, at least one big insurer has decided
not to cover the drug, labeling it as “experimental”, and another has put restrictions on exactly when it will pay for the drug.

Everyone has tremendous respect and compassion for muscular dystrophy patients. It’s a devastating diagnosis, a cruel genetic trick that unjustly burdens both its young victims as well as their families. While the approval of Exondys 51 was met with great joy by the Duchenne families, the response in the medical community was much more measured and critical. The fact that many voices inside the agency were overruled by Dr. Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research, was especially disconcerting. Her decision
did not sit well with some of her colleagues, who took the unusual step of appealing her decision to FDA Commissioner Robert Califf, MD. He declined to overrule her. The decision has led to internal agency friction and at least one staff departure. It also stimulated much discussion in the biomedical community, with numerous op-eds decrying the decision as both bad science and medicine. Many fear that the approval sets a bad precedent and will lead to the approval of other marginal or ineffective drugs, which could inhibit the development of other ones that might be more effective, safer, or both.

Whine, Complain, and Head to Europe
CTI BioPharma (formerly known as Cell Therapeutics, Inc.) has been around since 1991, and is still searching for a breakout drug. The company has struggled virtually over its entire existence and has never had a profitable quarter. The company’s cumulative shareholder deficit has reached an astonishing $2.037 Billion (yes, that’s billion with a B). Back in March of 2010, the company filed for FDA approval to sell its drug Pixantrone for use in patients with refractory non-Hodgkin’s lymphoma. The drug was unanimously rejected (9-0) by the FDA’s Oncologic Drugs Advisory Committee. The company was planning on enrolling 320 patients over a 36-month period for their pivotal phase III study, but after 45 months they had only enrolled 140 patients. The clinical data itself was also considered underwhelming for a number of reasons. Only eight of the patients had been treated in the U.S. Committee members raised concerns that these patients differed from those in Europe in their pretreatment regimens. There were also significant safety issues around neutropenia and cardiotoxicity.

The FDA acted on the panels vote and rejected the drug in April 2010. CTI decided to appeal this decision five months later under the FDAs Formal Dispute Resolution Process. The rationale: there was a lack of drugs available to treat relapsed/refractory aggressive non-Hodgkin’s lymphoma. In 2011, the company
paid a couple of lobbyists $30K to help get the drug approved via the appeal process. CEO Bianco is said to have predicted that its appeal would likely be successful, but the company pulled its application in January of 2012,“…because, after communications with the U.S. Food and Drug Administration, CTI needed additional time to prepare for the review of the Pixuvri (pixantrone) NDA by the FDA's Oncologic Drugs Advisory Committee at its February 9, 2012 meeting. Prior to withdrawing the NDA, CTI requested that the FDA consider rescheduling the review of the Pixuvri NDA to the ODAC meeting to be held in late March. The FDA was unable to accommodate CTI's request to reschedule, and given the April 24, 2012 Prescription Drug User Fee Act ("PDUFA") date, the only way to have Pixuvri possibly considered at a later ODAC meeting was for CTI to withdraw and later resubmit the NDA. CTI plans to resubmit the NDA in 2012.”

It didn’t happen. Instead, the company picked up its proverbial ball and headed to Europe, where they successfully gained approval of the drug (to be sold under the name Pixuvri) under a conditional marketing authorization. The company said,
“Similar to accelerated approval regulations in the United States, conditional marketing authorizations are granted in the EU to medicinal products with a positive benefit/risk assessment that address unmet medical needs and whose availability would result in a significant public health benefit. A conditional marketing authorization is renewable annually. Under the provisions of the conditional marketing authorization for Pixuvri, CTI will be required to complete a post-marketing study aimed at confirming the clinical benefit previously observe…As a condition of approval, CTI has agreed to have available the PIX306 clinical trial results by June 2015.”

Well, June 2015 has now come and gone. What did this trial show? Sorry, the results are not available yet. The company
announced in Jan. 2016 that they expect to complete enrollment in the PIX306 trial in the fourth quarter of 2016. And here's what the company had to say in their May 2016 10-Q filing: “As a part of the conditional marketing authorization, we are required to conduct a post-authorization trial, which we refer to as PIX306…Although we do not have and are not currently pursuing regulatory approval of PIXUVRI in the United States, or the U.S., we may reevaluate a possible submission strategy in the U.S. based on the data generated from the PIX306 study. Pursuant to our conditional marketing authorization in the E.U., we are required to submit the requisite clinical study report for PIX306 by November 2016. We plan to request an extension of such deadline.”

Let’s recap: in 2012 CTI said that it would have the PIX306 clinical trial results by June 2015. Now it’s saying it hopes to have enrollment completed by the end of 2016, and plans to file an extension on its obligation to complete the follow-up trial. Demand for the drug has been anemic; European sales of Pixuvri didn’t even bring in $1M during the second quarter 2016. Investors have clearly been underwhelmed by the company’s history of overpromising and then failing to deliver, and its share price is in penny-stock territory. This go-to-Europe strategy clearly didn’t pan out for CTI.

You may wonder why I’ve gone into such detail about CTI’s actions with Pixuvri. It’s because I’m afraid that this back-door approach may become much more common if a proposed piece of drug legislation passes. Senators Ted Cruz (R-Texas) and Mike Lee (R-Utah) introduced a bill in 2015, the Reciprocity Ensures Streamlined Use of Lifesaving Treatments Act (S. 2388, the RESULT Act). Among its
provisions are the following:
The HHS Secretary is instructed to approve a drug, device or biologic if the FDA confirms the product is:
- Lawfully approved for sale in one of the listed countries;
- Not a banned device by current FDA standards;
- There is a public health or unmet medical need for the product.
- If a promising application for a life-saving drug is declined Congress is granted the authority to disapprove of a denied application and override an FDA decision with a majority vote via a join resolution

This bill hasn’t become law yet, and hopefully never will. It might give companies (like CTI) a pathway to circumvent rejection of a drug in the U.S. by getting it approved (even if only conditionally) in Europe. That final clause also enshrines the idea that political judgments can to be used to overturn decisions based on science and/or medicine. Decisions made by the FDA, for better or worse, belong in the hands of its doctors and scientists (along with
input from patients and the public), not politicians. Do politicos think the FDA rejects potentially useful medicines just for the fun of it? This legislation is a really bad idea. Politics and biomedicine both have to deal with strong vocal advocates whose opinions are sometimes formed based on gut feelings that result from embracing mistruths and bad data. Sound science and unambiguous clinical data must be the bedrock on which FDA decisions stand. Wishes, feelings, and beliefs, no matter how heartfelt, cannot be allowed to Trump rational thought. John F. Kennedy was right when he said, “Too often we enjoy the comfort of opinion without the discomfort of thought.”

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