Drug Industry Daily - June 29, 2011 Issue

Vol. 10 No. 127

Jenkins: FDA Should Remove Avastin’s MBC Indication Despite Pending Trials

Allowing Genentech to finish conducting an additional Avastin trial before removing the drug’s metastatic breast cancer (MBC) indication “could undermine the integrity of the accelerated approval program,” FDA Office of New Drugs Director John Jenkins said Tuesday.

Jenkins made his comments at the first day of a two-day hearing on the agency’s move to rescind Avastin’s (bevacizumab) first-line MBC indication, received through accelerated approval. The required post-approval trials have failed to verify clinical benefit or prove the drug’s safety and efficacy in the indication (DID, July 19, 2010).

Genentech argues that “withdrawal is not appropriate unless the data establish that there is no longer a reasonable likelihood of clinical benefit and no meaningful way to characterize the potential benefit further,” Jenkins explained.

But that would be an unprecedented standard for withdrawal, Jenkins said, and the FDA cannot keep letting sponsors take “numerous bites at the apple” when “the totality of the available data shows that the modest effects of Avastin on progression-free survival do not outweigh its risks.”

Withdrawal of a drug that received accelerated approval “serves as a backstop to protect the public from continued marketing of a drug if clinical benefit is not confirmed,” Jenkins said. The FDA emphasized that the case meets the withdrawal standards outlined in the federal code of regulations.

“The law, the science and public health all consult against allowing the indication to remain on the label while Genentech conducts further studies,” Richard Pazdur, director of FDA’s Office of Oncology Drug Products, added.

Further, CDER says Genentech’s proposed confirmatory study is likely more than three years from completion and current data suggests the new trial wouldn’t substantiate clinical benefit.

The study Genentech is proposing is essentially a repeat of the E2100 trial — whose findings are the basis for the drug’s accelerated approval for the MBC indication. E2100 compared Avastin in combination with paclitaxel to paclitaxel alone. But an independent sponsor recently replicated the trial, and that trial, known as Study 10, failed to confirm the magnitude of PFS seen in the E2100 study, Jenkins emphasized.

Genentech will get a chance to refute CDER’s claims as the hearing continues Wednesday. The company has argued that while follow-up trials AVADO and RIBBON1 failed to meet their primary endpoint of improved PFS with a high degree of statistical significance, the drug’s benefit-risk profile remains favorable (DID, May 17).

“Genentech agrees with the many women and doctors who testified today in
support of keeping Avastin as an FDA-approved option for metastatic breast cancer,” the company said in a statement following the hearing’s first day. “Women with this incurable disease should have the option to choose this medicine.”

The Oncologic Drugs Advisory Committee is expected to issue advice and recommendations to the FDA at the conclusion of the second day.— Sarah Karlin


US Supreme Court’s Patent Involvement – It’s Just the Beginning

The U.S. Supreme Court — which has already seen an uptick in the number of drug-related patent cases it has heard in recent years — will continue to field more such cases, a former chief judge of the Federal Circuit said.

Justices decided three patent-related cases in its most recent term, which is winding up. But Paul Michel, who headed the U.S. Court of Appeals for the Federal Circuit from 2004 to 2010, only expects that number to increase in coming years.

During a panel on patent cases and the high court Tuesday at the Biotechnology Industry Organization (BIO) International Convention in Washington, D.C., Michel explained that an increased focus on healthcare within all branches of government and pending changes in patent law is driving that increase in interest.

“The Supreme Court’s involvement in patent cases is here to stay,” Paul Clement, former solicitor general under President George W. Bush, told the gathering.

Since the creation of the Federal Circuit in the 1960s for the express purpose of litigating patent cases, the Supreme Court has largely abstained in hearing those disputes.

However, in a paradigm shift, the court has recently agreed to accept more appeals on patent cases, particularly those that directly impact drugmakers.

Just this week, justices granted certiorari to a labeling carve-out dispute between Novo Nordisk and Caraco Pharmaceutical (DID, June 28).

The likely culprit of the shift in action has been the recent change in court makeup, suggests Thomas Hungar, former deputy solicitor general also serving the Bush administration.

Supreme Court Justices Sonia Sotomayor and Elena Kagan recently replaced retired Justices David Souter and John Paul Stevens.

Souter, in particular, has expressed support for as much legal protection for patent holders as possible, and the new justices carry different views on patent law.

“From what we’ve seen so far, neither of them come at patent law from the same perspective,” Hungar said. “It does seem as if Kagan and Sotomayor are having significant influence on the debate.”

Another change leading to more patent cases is the inevitable change in patent law now making its way through Congress, Michel said. Because this court has been more likely to strictly interpret laws, he said a change in language covering patents could mean more cases to interpret.

The House passed the America Invents Act last week, and now differences between it and the Senate-passed bill will be negotiated for both Houses to consider (DID, June 24).

But questions remain over how the Supreme Court will rule on drug-patent cases — if they do accept more.

A recent trend has seen the justices favor drugmakers, siding with Roche in a case earlier this month that determined whether a government-funded university researcher who invents products holds rights to products licensed to drug companies (DID, June 8).

Additionally, Justices sided with a patent holder in a dispute between technology companies in a ruling that would make it harder for generic-drug makers to overturn weak patents (DID, June 13).

It was difficult for panelists Tuesday to predict how the court will treat future cases because justices have ruled on so few to date.

“My belief is we’ll get more predictability and certainty that will come from the shared experience from seeing those cases,” Michel said. — David Pittman


Drugmakers Request Fewer Trials, More FDA Accountability, in Their Response to Regulatory Review

As the FDA conducts a comprehensive review of its existing regulations, industry is taking the opportunity to seek fewer clinical trials, and is asking for a revamp of the agency’s clinical hold policy and changes in its adverse event reporting policies.

Although FDA’s “substantial evidence” standard isn’t detailed in statute, the agency’s interpretation of the drug review standard is usually interpreted as requiring two “adequate and well controlled” studies. This is despite the fact that existing FDA regulation “allows significant discretion to approve drugs or biologics based upon a single trial.” The Biotechnology Industry Organization (BIO) says “FDA rarely exercises this flexibility.”

The trade group suggests that for unmet medical needs, rare diseases and other public health priorities, FDA should use its discretion and flexibility on a case-by-case basis in approving medical products to treat those dire conditions, it says in comments to the docket.

The FDA is conducting a comprehensive review of its existing regulations in response to Executive Order 13563, which mandated each federal agency periodically review its existing significant regulations to determine whether any such regulations should or could be modified to reduce the government’s financial burden. The FDA opened up a public docket that received comments through June 27 (DID, May 2).

The drug industry also has taken this opportunity to call for more accountability at the agency. For instance, FDA’s clinical hold policy should be revamped, drugmaker trade group PhRMA says, as it is “not followed consistently by FDA. There is little consequence for the agency if it fails to follow the policy,” the group says in its comments.

A clinical hold is an order issued by FDA to the sponsor of a drug application to delay a proposed clinical trial or to suspend an ongoing trial. The regulation states, “the FDA will, unless patients are exposed to immediate and serious risks, attempt to discuss and satisfactorily resolve the matter with the sponsor before issuing the clinical hold order.”

Industry, however, would like to see the FDA commit to making contact with a sponsor no later than five days prior to imposition of a clinical hold or suffer a consequence for not discussing and attempting to resolve the deficiency.

Improving adherence to this regulation would allow sponsors to make changes to Investigational New Drug (IND) applications so they could continue without costly study stops and resumptions, while protecting patients, PhRMA says.

While PhRMA didn’t point this out, clinical holds are often widely covered by the general press and can bring about poor optics for the drug company at issue.

Industry would also like to see increased international harmonization on several fronts, including adverse event reporting. FDA’s requirements for the reporting of adverse events that occur in clinical trials is inconsistent with requirements in the UK and the International Conference on Harmonization (ICH).

Not updating its adverse event reporting guidance “will lead to inconsistent adverse event reporting requirements and clinical data generation in the United States compared to the rest of the world,” PhRMA says.

Additionally, both groups express hope that this review of regulations will lead to the long awaited release of social media guidance. “Clearly, FDA’s promotional labeling and advertising regulations are outmoded and in need of immediate revision to reflect the 21st Century,” PhRMA says. “Given FDA’s use of technologies such as Twitter and Facebook to educate stakeholders about important events such as new drug approvals, clearly these media can be used in a responsible way.”

FDA officials repeatedly have noted that providing social media guidance is a leading priority. In the future the agency hopes to release as many as six guidances on the issue, Tom Abrams, director of CDER’s Division of Drug Advertising, Marketing and Communications, said recently. However, Abrams gave no release dates for the documents (DID, June 28). — Virgil Dickson


Generic User-Fee Negotiations to Continue Until End of July

Despite “general agreement” on many issues, further discussion is still needed on generic-drug user fees, so the FDA and industry have extended their negotiations until the end of July, according to minutes from a closed-door negotiation meeting held June 9 and made public Tuesday.

In May the FDA said negotiations between the FDA and industry, represented by the Generic Pharmaceutical Association and active pharmaceutical ingredient manufacturers, may well extend beyond the end-of-June time frame the parties had envisioned. But at that time they did not specify an end date (DID, May 11).

Overall, the agency and industry largely agree on many of the goals to be reached by the fifth year of the program. These include:

  • Risk-based inspections with parity for domestic and foreign reviews;
  • Time frames for the review of applications with inspection metrics;
  • The need to prepare databases for collecting fees and attaining goals; and
  • The need to raise filing standard to induce more quality applications.

“However, there are still areas that require further discussion to reach agreement on goals,” the minutes note.

For example, the FDA and industry disagree on how to show progress during the early years of a program, “before a full complement of additional staff can be hired and trained to fill productivity,” the minutes note.

During the May 26 negotiations, the FDA shied away from setting performance goals during the early years of a user-fee program, saying it would need to focus on hiring staff (DID, June 15).

Performance metrics for the first two years of a generic-drug user-fee program “would not be obtainable due to the historical underfunding” of generic drug review, the FDA reiterated during the June 9 meeting.

Instead, the FDA offered other ways to show the progress of the program during its early years, including using complete response letters as well as division-level deficiency reviews to offer feedback and rolling reviews with telephone meetings.

For its part, industry agreed to concede performance metrics “across the board” for the first two years of the program if, in exchange, the “agency could strive to maintain review performance” throughout those initial years.

Further discussion is also needed on “interim goals prior to year five of the program,” and on ways to “incentivize quality applications and limit amendments,” according to the minutes.

While both parties agreed that generic-drug makers need to increase the quality of their submissions, industry expressed concern over the agency’s plan to avoid establishing review metrics for unsolicited amendments.

A refusal to include metrics for unsolicited amendments could penalize quality applications that are forced to file an amendment due to an unforeseen change in an ANDA, industry argued.

The next closed-door generic-drug user-fee negotiation meeting was scheduled for June 24, but its minutes have not yet been posted publicly. The docket, FDA-2010-N-0381, will remain open until Aug. 1. — Kevin O’Rourke


Novartis’ Use of Priority Review Voucher Could be a Wash

Last week’s Arthritis Drugs Advisory Committee vote against recommending approval of Novartis’ Ilaris to treat gouty arthritis attacks may be doubly disappointing, as the company used its priority review voucher, a unique advantage, to jumpstart the product’s review.

Novartis received the voucher via its April 2009 approval of malaria drug Coartem (artemether/lumefantrine). The voucher allows a drugmaker to pay for a drug to be approved within six months versus a regular 10-month review (DID, Sept. 15, 2010).

Novartis had to pay $4.6 million in addition to the normal user fee of $1.5 million to redeem its voucher for Ilaris (canakinumab, or ACZ885). The company is the only drugmaker to receive and use such a voucher, created under a program in the FDA Amendments Act to encourage drugmakers to develop drugs to treat tropical diseases with high unmet need.

However, the June 21 advisory panel concluded that Ilaris’s efficacy does not outweigh its safety concerns. The panel also voted unanimously that the clinical data do not support a labeling claim that Ilaris can reduce the frequency of gouty arthritis attacks (DID, June 22).

Ilaris was originally approved in 2009 to treat a rare and sometimes life-threatening auto-inflammatory condition, cryopyrin-associated periodic syndrome (CAPS) (DID, June 19, 2009).

Analysts have forecast Ilaris’ U.S. sales in the $100 million to $125 million range; however, the advisory committee recommendations may put those projections in doubt. — Sarah Karlin


Denosumab Likely PDUFA Date for CRPC is Dec. 27

A December Prescription Drug User Fee (PDUFA) date is likely for Amgen’s sBLA to obtain a third indication for denosumab, this time to treat men with castrate resistant prostate cancer (CRPC) to reduce the risk of bone metastases.

If approved, denosumab (trade name Xgeva) would be the first therapy licensed to prevent or delay the spread of cancer to the bone, according to the large-cap biotech. With this unmet need in mind, a priority, or six-month, review is likely and that would place the user fee action goal date at Dec. 27.

“Xgeva has the potential to become a significant advance for patients with castrate-resistant prostate cancer who currently have no treatment options to help prevent the spread of cancer to their bones,” Roger Perlmutter, executive vice president of Research and Development at Amgen, says.

The submission is based on Phase III trial Xgeva improved median bone metastasis-free survival by 4.2 months, and delayed the time to first bone metastases by 3.7 months in 1,432 men with CPRC. Overall survival was similar between both those receiving Xgeva and patients receiving placebo (DID, May 19).

Bone is one of the most common places for cancer to spread. In fact, up to 90 percent of men with advanced prostate cancer will have their tumor spread to the bone, Amgen says.

Denosumab was approved in June 2010 with the trade name Prolia for the treatment of women with postmenopausal osteoporosis at high risk for fracture. In November it received approval as Xgeva for prevention of skeletal fractures in patients with solid tumors.

Sales of denosumab last year were $41 million. Through March 2011, the drug posted $69 million worldwide in all indications.

If approved, the new indication is expected to be “a significant driver of Xgeva sales growth,” Oppenheimer & Co. analyst Bret Holley said in a note published Tuesday. Sales of the drug in the prevention of bone metastases could reach $880 million by 2015, he added.

When Xgeva was approved last year, analysts had projected sales of $172 million in 2011 and $565 million in fiscal 2013 (DID, Nov. 22, 2010). Baird’s Christopher Raymond, more sanguine, expects 2011 denosumab revenue to land around $344 million. Most analysts expect the drug to hit blockbuster status within a few years.

Physicians are already expressing interest in the drug as a way of stopping the spread of cancer to bones. J.P. Morgan recently surveyed 25 community urologists and of those who participated, 88 percent viewed a 4.2-month improvement in metastasis-free survival as clinically meaningful and 100 percent of doctors viewed the endpoint as “important.” — Virgil Dickson

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