DID - Sept. 10, 2008 Issue

Vol. 7 No. 177

Process Validation Guidance to Focus on Testing Upfront

The FDA will emphasize more oversight and batch testing in the early stages of drug commercialization in its revised guidance on process validation, according to Brian Hasselbalch, a consumer safety officer in CDER’s Division of Manufacturing and Product Quality.

“The guidance acknowledges that a great deal of knowledge is going to be gained in the first year or two of commercial production. Consequently, we’ll expect more attentiveness in that stage,” Hasselbalch said Tuesday at the Parenteral Drug Association-FDA Joint Regulatory Conference in Washington, D.C.

If companies follow the guidance as it is intended, they will conduct more oversight and testing on the first commercial batches to ensure their control strategy is appropriate, he said.

Hasselbalch, the team leader for good manufacturing practice guidance and policy development, said the revised guidance could be released within one or two months. It has cleared all FDA centers involved — CDER, CBER and the Center for Veterinary Medicine — and approval by the agency’s legal division is the remaining hurdle. The guidance will replace the FDA’s 1987 process validation guidance.

Under the revised validation guidance, running three process validation batches and sampling 10 units from each batch is not sufficient, Hasselbalch said.

“The kinds of questions we’re expecting that companies will ask these days is, ‘Do I have confidence?’ And by that we mean statistically sound confidence in your process,” Hasselbalch said. “You’re probably going to have a statistician or two or three [telling you] what that means for the product and process.”

The FDA expects companies to understand processes before a product is distributed with rapid assurance after the first batch is released commercially, he said.

“You’re probably going to have to sample more of each batch, and you’re going to have to sample more batches. But … whatever the statistician says gives you a sufficient level of confidence,” Hasselbalch said.

Statistical Confidence

Hasselbalch did not directly answer an audience question regarding what the FDA considers an adequate level of statistical confidence, but he agreed that risk assessments of critical quality attributes might suffice.

He also said the FDA decided to set aside other topic areas in the guidance, such as statistical quality control or the use of statistics in process validation. Those topics will be discussed in additional guidance later.

The modified process validation guidance requires comprehensive process design and recommends incorporating risk management techniques into validation.

“By that, we mean we’re going to essentially allow companies to take some risk,” Hasselbalch said. “We’ve always acknowledged that risk is a part of it. What we mean, though, is that we expect your risk to be based on a more formal assessment and understanding of what that risk is. In other words, you might delay addressing a possible failure mode, for example, because it just doesn’t rank that high in a ranking exercise.”

However, “we expect you to address all possible significant failure modes,” he added. “But the timing of it … can be adjusted.”

What Will Change

Hasselbalch said not much would change for biologics under the revised process validation guidance.

For drugs with a small market share, the production of batches that would not be distributed — yet are recommended by process validation statistical assessments — would not be necessary to satisfy FDA requirements.  

“We’ve acknowledged that there are times that you don’t need them [additional batches] in the sense that maybe it’s an orphan drug or it just has a small market share … or a potent compound,” Hasselbalch said. “We don’t want you to make batches to satisfy validations per se. However, I would want you to scale the process in accordance with your needs.”

In situations with low-volume products in which only one batch is made every six months, that batch can be released but with enhanced sampling and stricter market monitoring, he said.

When asked whether the guidance applies to drugs on the market, Hasselbalch said it was written with a prospective nature in mind and the FDA expects firms to use it for products in development.

He said the FDA was releasing this guidance because some firms were “gaming” process validation — producing batches without gaining process understanding. — Christopher Hollis


Justice Official: First Amendment Does Not Protect Off-Label Claims

Drugmakers should not contend they have a First Amendment right to make claims about the off-label uses of their products, a Justice Department official advised.

“If you say things that are not true or are misleading in a commercial context, that’s not a First Amendment issue. If the sales script says things that aren’t true or are misleading, that’s a problem,” Jeffrey Bucholtz, principal deputy assistant attorney general in Justice’s Civil Division, said at a panel discussion at the Food and Drug Law Institute conference in Washington, D.C.

The HHS Office of Inspector General (OIG) and Justice will investigate drugmakers engaged in “multiple types of egregious conduct” rather than off-label promotion alone, Mary Riordan, senior counsel with OIG’s Administrative and Civil Remedies Branch, said.

Many drug companies settle off-label promotion cases because of the “atomic weapon” of threats that they will be excluded from participating in federal healthcare programs, Lynn Shapiro Snyder, a defense attorney and senior member of Epstein Becker & Green, said. “I’m terrified about the application of the False Claims Act to off-label promotion,” Snyder said Tuesday.

Bucholtz cited prosecutorial discretion. “Just because we have evidence of a provable criminal case doesn’t mean we’ll bring it,” he said. “We would consult with the FDA before bringing a case in this area. If the FDA concludes it was defrauded before, that’s one thing. But if the agency stands by a previous evaluation [because a company has cooperated with a probe], that’s different.”

Another argument that doesn’t impress Justice is that “the company is only trying to engage in full scientific dialogue and knows best about its own products,” Bucholtz said. “That sounds nice, but we often have detailers communicating these messages in a way that is not scientific.” Science is “full of caveats,” and these must be passed on to prescribing physicians, he added.

Pharmaceutical sales staff should not present drug data to physicians in a misleading way, he said. Presenting preliminary study results while explaining the limitations may be fine, but a press release that focuses on positive data may not be acceptable.

The worst cases involve situations in which the FDA has rejected a company’s application for a given indication of a drug but the company promotes its use. Any indication of possible kickbacks that violate the Anti-Kickback Statute also is a red flag.

Drugmakers may not be allowed to argue that only a few rogue salespeople engaged in off-label promotion. “I urge companies to pay attention to the tone from the top down to ensure compliance,” Riordan said.  “Often there’s trouble if there is a conflicting message of compliance that cannot be achieved with the marketing programs that are set up.

“There has to be accountability. It’s not just the compliance officer’s job to assure compliance. It has to start at the board level and filter all the way down to line-level employees. Integrate compliance into the business practices of your company.”

The panel offered the following tips on off-label drug promotion:

  • Do not send salespeople to market a drug to specialist physicians who cannot prescribe it for its labeled indication. “That is evidence of intent on the company’s part,” Bucholtz said;
  • When the FDA issues a draft guidance that deals with drug-marketing companies that disagree, be sure to file comments to “at least be on record as to why you were against it,” Snyder said; and
  • Offer internal auditing and training, which is often best accomplished in person and in small groups. — Martin Gidron


Forest Warned by FDA for Deceptive Claims in Advertisement

An advertisement for Forest Laboratories’ Bystolic minimizes the risks associated with the medicine and says it is superior to rivals, according to an FDA warning letter that tells the company to immediately stop distributing such claims.

The FDA’s Division of Drug Marketing, Advertising and Communications says the company’s Bystolic (nebivolol HCl) tablets are misbranded because the eight-page ad implies the drug has superior beta-adrenergic receptor blocking agents to treat hypertension and that Forest has established the drug’s anti-hypertensive abilities — claims not listed in labeling approved by the agency.

In the ad published in medical journals when the product launched in January, the company calls Bystolic a “next generation beta blocker” and says its “unique mechanism of action includes cardioselective beta blockade and vasodilation.”

According to the Aug. 28 letter posted Monday on the FDA’s website, “These and similar presentations are misleading because they imply that Bystolic’s efficacy and mechanism of action make it superior as an antihypertensive to other [beta-adrenergic] receptor blocking agents.”

The FDA adds that it is not aware of any studies comparing Bystolic with other beta blockers or of any data that would render the drug’s mechanism of action unique.

A footnote in the Forest ad states that Bystolic’s mechanism of action for the anti-hypertensive response has not been definitively established and lists the drug’s possible side effects. However, the letter says the footnote is insufficient to offset the misleading implications created by the claims in the body of the ad.

Additionally, the ad includes a header that says, “Efficacy demonstrated across a broad range of patients” with bullets underneath listing subgroups of patients who are obese, poor metabolizers and diabetic. However, the FDA was only aware that effectiveness was established in black hypertensive patients and was similar in subgroups analyzed by age and sex, according to the letter.

“Therefore it is misleading to imply that efficacy was demonstrated in these subgroups when this has not been supported by substantial evidence or substantial clinical experience,” the letter says.

The ads are no longer in circulation, according to a Forest spokesman. The FDA asked for a response to its letter on or before Sept. 12. The company plans to respond by that date. The letter is available at www.fda.gov/cder/warn/2008/Bystolic-wl.pdf. — Renee Frojo


Pfizer Pulls Dalbavancin Applications to Conduct More Trials

Pfizer is withdrawing all marketing applications for its dalbavancin drug to treat infections in adults including methicillin-resistant Staphylococcus aureus (MRSA) following discussions with regulatory authorities.

The company plans to conduct an additional global, multicenter, Phase III clinical trial with dalbavancin to treat adults with complicated skin and skin structure infections caused by gram-positive bacteria. The study will generate additional clinical data to support future regulatory submissions. A pediatric program with dalbavancin also is planned, Pfizer says.

“After careful consideration of feedback and ongoing dialogue with regulatory authorities, Pfizer has decided to study dalbavancin further in patients with complicated skin and skin structure infections,” Mark Kunkel, Pfizer’s global medical therapeutic area leader for anti-infectives and HIV, says in a statement. “Dalbavancin represents a potential important treatment advance and Pfizer is committed to ongoing research of its use in patients who suffer from serious skin infections, including those caused by MRSA.”

Pfizer obtained rights to dalbavancin, a member of the glycopeptide class of antibiotics, through its September 2005 purchase of Vicuron Pharmaceuticals. It also acquired the rights to the anti-fungal Eraxis (anidulafungin) in the deal. Approved in February 2006, Eraxis is used to treat certain infections caused by candida (DID, Feb. 22, 2006).

The dalbavancin application has hit previous roadblocks. In June 2006, Pfizer received an approvable letter for the drug related to the chemistry, manufacturing and controls section of its NDA.

Last December, the company received an approvable letter for the drug (DID, Dec. 27, 2007). In announcing the FDA’s action, the company implied that the agency wanted more information in connection with a guidance document that discourages noninferiority studies for antibacterial agents (DID, Oct. 31, 2007).

The approvable letter referred to deviations from current good manufacturing practices at a third-party manufacturer not specifically related to dalbavancin. Pfizer also had to address a question from the FDA regarding length of storage time following reconstitution of the drug. — Elizabeth Jones


Avoiding Conflicts When Funding CME or Promotional Education

Drugmakers seeking to avoid conflicts of interest while supporting medical education for doctors should finance independent, certified programs, an expert says.

“There’s a difference between promotional education and certified” continuing medical education (CME), John Kamp, executive director of the Coalition for Healthcare Communication and a lawyer with Wiley Rein, said.

In CME, drug companies may control the funding, but they do not control the message, Kamp said at the Food and Drug Law Institute’s conference on advertising and promotion in Washington, D.C.

CME programs are independently accredited by the Accreditation Council for Continuing Medical Education, the American Academy of Family Physicians, the American Medical Association and other organizations.

CME is the top influence on physicians’ prescribing habits, Jennifer Smith, executive director of medical education at Wyeth Pharmaceuticals, said. “It’s appropriate that physicians use CME in deciding how to prescribe. What would be inappropriate is improper influence by commercial sponsors, and that’s what people are concerned about,” she added.

“The FDA does not differentiate between education and promotion; it differentiates between independence and non-independence,” Pamela Mason, director of the medical education grants program at AstraZeneca, said. “They have been clear that if industry controls the content and the speakers, then it is promotion and it should be regulated.” Promotional education usually has a product-specific content focus, and learners participate to learn about new products and meet interesting faculty members, she added.

Almost half of the $2.51 billion a year spent on CME in the U.S. comes from the industry, Hilary Schmidt, associate vice president of medical education at Sanofi-Aventis, said. Last year, more than 14.7 million people participated in CME, collectively receiving more than 740,000 hours of instruction.

In independent, certified CME, the educational institution sets the standards and selects the faculty, but funding may come from a commercial interest, Mason said. Such programs are usually focused on specific diseases and present scientific data.

It’s vital that the pharmaceutical industry continue to fund CME so physicians can learn about disease treatments, Schmidt contended. For example, a recent study by Sanofi-Aventis showed that physicians’ use of bone density tests increased 12-fold after a CME course.

“Pharmaceutical companies receive far more requests for assistance than we can honor,” she added. “At Sanofi-Aventis, the number of requests we fund has dropped to 30 percent; at other companies, it may be 60 percent.”

In 2003, the HHS Office of the Inspector General said grant decisionmaking by drugmakers should be made separately from sales and marketing decisions, and sponsors must ensure they are supporting bona fide educational activities, Mason said.

It can be difficult to decide what CME information the sponsoring companies should disclose, Schmidt said. Amounts of funding, recipients and titles are vital, but there may be more than one recipient per grant, and “a lot of activities are supported by multiple sponsors,” she said. Another problem is that drugmakers’ CME tracking systems were not designed for reporting, so it’s not always simple to extract needed data.

Recent corporate integrity agreements, such as the one imposed on Bristol-Myers Squibb last year, have underlined such requirements. The company agreed that:

  • All CME activities it supports will be transparent;
  • There will be a quarterly documentation review of 10 randomly selected grants;
  • The occurrence of all CME activities it funded will be verified; and
  • Records of CME activities will be maintained. –– Martin Gidron


Novartis Cancer Drug to Get Priority Review

The FDA has granted priority review to Novartis’ kidney cancer treatment RAD001, an investigational drug being studied in multiple tumor types.

Novartis has filed the RAD001 (everolimus) application with U.S., EU and Swiss regulators. The proposed name for the drug, Afinitor, has been accepted by the European Medicines Agency and is under review in the U.S.

The applications are based on data from the Phase III RECORD-1 trial, the interim results of which were published in The Lancet July 23.

An independent data monitoring committee stopped the trial in February after results showed that patients receiving RAD001 experienced a significant response compared with those on placebo. RAD001 more than doubled the time without tumor growth from 1.9 months to four months after failure of previous targeted treatment in patients with renal cell carcinoma. It also reduced the risk of disease progression by 70 percent.

Study data showed that 45 percent of patients who received RAD001 experienced progression-free survival beyond five months, according to Novartis.

Everolimus is available in different dosage strengths under the trade name Certican to prevent organ rejection in heart and kidney transplant recipients. Certican was approved in the EU in 2003.

In addition to renal cell carcinoma, RAD001 is being evaluated as a single agent or in combination with existing therapies in neuroendocrine tumors, tuberous sclerosis, lymphoma and breast, gastric, lung and other cancers. — Elizabeth Jones


Texas AG, Abbott Settle in Medicaid Lawsuit

Texas Attorney General Greg Abbott has reached a $28 million civil settlement with Chicago-based Abbott Laboratories resolving a four-year dispute over whether the drug manufacturer falsely reported drug prices to Medicaid.

Ven-a-Care of the Florida Keys brought the scheme to the state’s attention and became a plaintiff in the case. It will receive $2.8 million as part of the settlement agreement.

Under state and federal law, drug manufacturers must inform the Medicaid program about pricing plans they offer to pharmacies, wholesalers and distributors. The program uses this information to estimate the amount pharmacies pay to acquire the drugs. Pharmacies bill the program for these costs and dispensing fees, and Medicaid reimburses them based on the manufacturer-reported prices.

Because Abbott allegedly reported false prices of various IV fluids and other products, Medicaid reimbursed pharmacies at inflated rates. The reporting dates back to the 1990s, according to the attorney general’s office.

Under the agreement, Texas will receive about $18 million in damages and $10 million in attorneys’ fees and costs. Abbott denies all of the plaintiffs’ claims and allegations but will settle to “avoid the delay, uncertainty, inconvenience and expense of protracted litigation of these disputed claims,” according to court documents.

Texas has settled civil Medicaid fraud cases against several companies, including Dey in June 2003 for $18.5 million, Schering-Plough and subsidiary Warrick Pharmaceuticals in May 2004 for $27 million total, Boehringer Ingelheim and its subsidiary Roxane Laboratories in November 2005 for $10 million total and Baxter Healthcare in June 2006 for $8.5 million.

Enforcement actions against several other manufacturers, including Alpharma, Barr Pharmaceuticals, B Braun Medical, Par Pharmaceutical and Watson Pharmaceuticals, are pending (DID, July 11). — Elizabeth Jones

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