Medical Dynamics

FDA Clears Hologic’s MammoSite ML Radiation Therapy System for the Treatment of Early-Stage Breast Cancer (Media Exhange)

 Human Genome: Journal Reviews Lupus Drug Endpoints Positively (Dow Jones)

NovaDel Article Published in Headache: The Journal of Head and Face Pain (Business Wire)

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The Pink Sheet “For Generic Vancocin, An Advisory Committee Role Reversal” August 3, 2009

The Pharmaceutical Science and Clinical Pharmacology Advisory Committee does not typically review specific drugs. But on Aug. 4, FDA’s Office of Generic Drugs will ask the committee for its advice on bioequivalence standards for ViroPharma’s Vancocin (vancomycin).

Currently OGD recommends that an applicant seeking marketing approval for generic vancomycin demonstrate bioequivalence to Vancocin through in vitro dissolution studies.

According to FDA’s briefing documents, Vancocin – which is indicated to treat staphylococcal enterocolitis and antibiotic-based associated pseudomembranous colitis caused by Clostridium difficile – is highly soluble over a wide range of pH values and acts locally in the GI tract. For this reason, comparing dissolutions rates in media of varying pH values which represent conditions in the GI tract is the most suitable approach for comparing generic vancomycin and Vancocin.

ViroPharma, however, argues that those requirements are essentially the Biopharmaceutics Classification System-based biowaiver, which was developed using healthy GI parameters to predict the absorption of systemically acting drugs from the healthy gut and was not intended for use in predicting in vivo performance of locally acting GI drugs.

In addition, the dissolution standard does not address the conditions of the in vivo environment of the diseased GI tract in which Vancocin is used, the brand firm argues. The generic’s dissolution and solubility would never be studied using relevant physiological conditions, including decreased fluid volumes, elevated pHs, and altered fluid composition.

In 2006, FDA issued BE recommendations for vancomycin capsules in a draft guidance, changing the standard from clinical endpoint studies to the in vitro dissolution BE method for BCS Class I drugs based on academic inquiry into the physiologic parameters of the healthy human GI tract. In light of that evidence, FDA waived the requirement that BE must be demonstrated with in vivo data.

Of the four BCS drug classes, FDA has extended the biowaiver to only BCS Class I drugs. In 2006, Vancocin was characterized as Class I and deemed eligible for a biowaiver.

However, ViroPharma insists that Vancocin is not a BCS drug at all. The BCS explicitly did not consider locally acting drugs such as Vancocin in its validation development, it argues, and furthermore, Vancocin is not rapidly dissolving.

Both FDA and ViroPharma’s briefing documents note that the shift to in vitro dissolution BE for vancomycin relied in part on faulty data from a generics company that showed vancomycin is rapidly dissolving. ViroPharma objected to the data and when FDA took a closer look, it confirmed that vancomycin is not rapidly dissolving.

In March of 2006, ViroPharma filed a petition with FDA, seeking to stay approval of all ANDAs that reference Vancocin, saying acceptance of in vitro bioequivalence standards was “fatally flawed” and should not have been issued without prior public discussion.

Most recently, ViroPharma has taken the unusual step of challenging the assertions in the agency’s briefing documents – most importantly the fact that Vancocin was approved based on dissolution studies, a point the sponsor emphatically denies. Other inaccuracies, according to a ViroPharma letter sent to the docket on July 31, include OGD’s misrepresentation of a historical document and misconstruing key facts regarding acarbose ANDAs.

When the committee met last summer to discuss bioequivalence, ViroPharma treated the panel as a make-or-break event in trying to convince FDA to change its approval standards.

During that meeting, ViroPharma was relegated to presenting data during the open public hearing, but this time the company will get equal billing as a presenter, although generic firms may present as well. But the fact that ViroPharma is inching its way up the agenda, instead of having to face generics in the marketplace, could be a sign that it’s making progress to get FDA to change its mind.

The Pink Sheet

“Schering Plough’s Saphris Gets Strong Nod From FDA Panel”

July 31, 2009

The atypical antipsychotic market should soon be seeing competition from a new entry with a novel formulation and a more attractive safety profile, after an FDA advisory committee voted strongly in favor of Schering Plough’s Saphris (asenapine) for acute schizophrenia and bipolar mania in adults at a July 30 meeting.

The Psychopharmacologic Drugs Advisory Committee found asenapine to be similarly efficacious to others in the atypical antipsychotic class and have a slightly better safety profile. The FDA panel voted unanimously that the risk-benefit balance was positive for the bipolar indication, and 9-1 with 2 abstentions that the balance was positive for schizophrenia.

They sited similar efficacy to other antipsychotics, a slightly better safety profile, the need for further treatment options for the difficult-to-treat patient populations, and the benefit of asenapine’s formulation as a sublingual tablet for patients that have trouble swallowing pills.

The sponsor did not come into the meeting facing an uphill battle. In briefing documents released prior to the meeting FDA stated its support for the safety and efficacy of asenapine compared to rest of the atypical class. And breaking with typical advisory committee protocol, the agency did not even make its own presentation of the data, instead saying it supported the sponsor’s conclusions

For the risk side of the equation in both indications, asenapine made a strong showing against a class of atypical antipsychotics known for a host of safety and tolerability issues.

Asenapine was not associated with any new or unexpected adverse events, and even demonstrated less impact on weight and metabolic parameters than some of its would-be competitors, including Lilly’s Zyprexa (olanzapine) and Johnson & Johnson’s Risperdal (risperidone), both of which served as active controls in the development program.

In terms of efficacy, the panel found it easier to vote on the bipolar indication than schizophrenia, voting unanimously that the bipolar studies were clearly positive for asenapine.

The primary concern pertaining to asenapine in bipolar disorder pertained to dose, and whether the drug could be efficacious at the 10 mg BID dose at which it was studied. Schering told the panel it is committed to conducting a postmarket study of asenapine at 5 mg BID for bipolar disorder.

Votes on the schizophrenia indication were a bit more scattered due to some confusion of how to interpret the overall efficacy signal over four trials. Two of the trials were positive for asenapine, but only one was positive for the dose the firm is proposing: 5 mg BID. The other trial tested asenapine at 10 mg BID, showing similar but no additional benefit to the 5 mg dose.

Of the other two trials, one was discounted as a failed study (showing no benefit for either asenapine or the active control against placebo) and the other was negative (with the active control, but not asenapine, superior to placebo).

Ultimately, they voted 10-2 that asenapine was effective for schizophrenia, comparable to other atypical antipsychotics. The two members who voted against approval cited concerns about the mixed signals across the trials, and the 60 percent drop-out rate in one of the trials (an attrition rate FDA said was typical for psychiatric trials).

The panel also voted 10-2 that the safety profile for the schizophrenia indication was acceptable, after determining that a vote against efficacy must logically lead to a vote against safety, despite a risk profile positive in comparison to others in the class.

In addition to the lower-dose study of asenapine in bipolar disorder, Schering assured the panel that it is also committed to conducting post-market pediatric studies for both indications.

The Pink Sheet

“Can Pharma Industry Afford To Give Up More For Health Reform? PhRMA Says President “Misinformed””

July 30, 2009

President Obama is “misinformed” in his opinion that the pharmaceutical industry can afford to make more drug price sacrifices as part of health care reform, the Pharmaceutical Research and Manufacturers of American said.

In an interview, PhRMA Senior VP Ken Johnson responded to a question about Obama’s assertion, made most recently during a July 28 town hall meeting sponsored by AARP, that “we can get potentially an even better deal than” the $80 billion in drug price discounts the industry previously agreed to with the Senate Finance Committee and the White House.

“Unfortunately, the president is misinformed,” Johnson said. “The simple fact is our companies are making a significant financial contribution to health care reform that comes with some consequences. This is $80 billion coming off our companies’ books, and there’s going to be some accompanying pain. This is going to require our companies to make some difficult decisions in moving forward, but at the same time if health care reform is passed and the agreement remains in place, it provides our companies with some certainty to make the kind of long-term R&D decisions that are important to our companies.”

Regarding Obama’s claim at the AARP event that American’s pay 77 percent more for drugs than people in other countries, Johnson said “it’s not a figure we’ve heard before,” although he noted it is generally recognized that drug prices in other countries are often lower because they have price controls.

It is also unfair to assume that pharmaceutical companies will reap a windfall in profits through an expansion of health care coverage, Johnson said.

He said that about 60 percent of the currently uninsured are 35 years old or younger, a population that does not take a lot of prescriptions, that the majority of the newly covered are likely to get generic drugs and that patients who paid full retail price when they were uninsured will get drugs at prices set by Medicaid or negotiated by private insurers once they are insured.

“Our best estimate of the net impact on industry revenues [from coverage expansion] is pretty modest, ranging from a potential upside of about 1% to a loss of about 2% depending on who you talk to,” Johnson said, “but there are absolutely no facts out there to support the notion that this agreement will lead to a windfall for the industry. That’s simply not true.

Still, Johnson said PhRMA believes the $80 billion agreement “is the right thing to do if it ensures that every American has access to high quality affordable health care coverage and services. It’s part of the shared sacrifice that we believe is necessary.”

PhRMA will be running ads in support of passing comprehensive health reform over the August recess in states where its members “have a significant economic footprint,” such as California, Illinois, Indiana, New Jersey and North Carolina, Johnson said.

The Energy and Commerce Committee resumed markup of the House reform bill July 29 after postponing the proceedings for over a week to resolve disagreements with fiscally conservative Blue Dog Democrats on the committee.

The Pink Sheet

“Schering’s Antipsychotic Saphris Should Have Easy Advisory Committee Review”

July 29, 2009

FDA appears to be looking to its Psychopharmacologic Drugs Advisory Committee for the final nudge toward approving Schering-Plough’s atypical antipsychotic Saphris (asenapine) for schizophrenia and bipolar disorder in adults.

In briefing materials released prior to the July 30 meeting, the agency states that it hasn’t yet made a final conclusion on the application, but makes it clear that it doesn’t have any problems with it.

“We generally are in agreement that the sponsor has provided adequate support to suggest effectiveness for asenapine for the claimed indications,” FDA Director Division of Psychiatry Products Tom Laughren writes in briefing documents.

“In addition, we view the safety profile for this product in the populations studied to be qualitatively similar to that observed for other atypical antipsychotic drugs, and to be acceptable. Chemistry, toxicology, and biopharmaceutics issues for the application have also been resolved, and we are currently discussing proposed labeling for the product with the sponsor.”

Breaking with standard procedure, FDA won’t even be making a presentation at the meeting, “since we are in essential agreement with the data to be presented by the sponsor,” the briefing documents state.

Nevertheless, the panel will be asked to weigh in on the safety and effectiveness of asenapine for both indications.

If approved, asenapine would join an already crowded antipsychotic class. But the limitations of currently available treatment options show FDA more amenable to approving still further treatments than once thought.

All atypical antipsychotics are effective only in a subset of patients that can’t be predicted prior to treatment, and come with a host of safety and tolerability issues, including somnolence, weight gain, increases in blood lipids and glucose, acute extrapyramidal symptoms and tardive dyskinesia.

Schering-Plough writes in briefing materials that in terms of those common safety problems, asenapine showed limited effects on weight, metabolic laboratory parameters, orthostasis and prolactin levels, and that the drug has a low propensity to induce EPS, has no increased risk of suicidality and no clinically relevant effects on the QT interval or liver parameters.

The clinical development program included 2,251 subjects in Phase II/III studies. Of those, 252 were exposed for at least 26 weeks and 225 for at least a year.

“As such, asenapine is a promising alternative to existing approved therapies,” the firm writes.

The agency issued a “complete response” letter for the application earlier this year requesting supplemental data. The company turned the letter around in just over a month.

Asenapine is formulated as a fast-dissolving tablet for sublingual administration.

The Pink Sheet
“FDA Giving King’s CorVue A Chance Despite Failed Trials”
July 28, 2009

Despite running three failed trials, FDA appears to be giving King the benefit of the doubt and seeking committee input on whether it should evaluate the pharmacological stress agent CorVue (binodenoson) based on modified efficacy criteria.

Members of FDA Cardiovascular and Renal Drug Advisory Committee do not have an easy task ahead of them at their July 28 meeting. In addition to variability among imaging tests used in its studies, King also changed the primary endpoint of two out of three pivotal studies after it had reviewed results from the first, and chose not to follow FDA guidance for developing medical imaging drugs.

FDA determines efficacy of diagnostic imaging agents on performance characteristics (sensitivity and specificity) relative to a truth standard, or on the extent of agreement between the investigational test and a reference test.

“High agreement between a new test product and a reference product can support a claim that the new test is an acceptable alternative to the reference product,” the guidance notes.

The Phase III studies of CorVue (studies 301, 302 and 305) evaluated similarity of CorVue single photon emission computerized tomography myocardial perfusion imaging and the most frequently used pharmacological stress agent, Astellas’ Adenocard (adenosine) SPECT MPI images. One study (305) also evaluated the extent of agreement of two sequential Adenocard SPECT MPI images.

The set primary endpoint for the studies was a kappa statistic for categorized summed difference scores (SDSs) of individual patients in the study arms. However, after review of the results of study 301, King changed the efficacy analysis plan for the ongoing studies to an equivalence comparison of the mean SDSs of the two drugs.

The agency informed King that it did not agree with the changes, and that it viewed the new analysis as exploratory or supportive at best. Of particular concern was the extent of CorVue/Adenocard agreement and the specific analytical methodology necessary to verify that the study drugs did not importantly differ in efficacy.

Of the three Phase III studies, one failed to achieve its primary endpoint (a weighted kappa statistic) while two achieved the modified primary endpoints (a comparison of mean SDSs). The “original” primary endpoint was not achieved in any of the studies, conceivably due to the test-retest variability of SPECT MPI.

King notes the variability of SPECT MPI in its briefing documents, summarizing that they include biological variability in coronary vasodilatory response to Adenocard receptor stimulation, variability in extraction and myocardial uptake of the radiopharmaceutical, image acquisition variability, and interpretive variability.

According to FDA, the performance of CorVue and Adenocard appeared to be numerically similar in the subset analyses, and the clinical safety showed that the incidence of clinically important cardiovascular adverse reactions to CorVue was lower than the incidence of reactions to Adenocard.

FDA’s review of the clinical data is ongoing, but in briefing documents they stress concerns that “the available data do not exclude the possibility that CorVue SPECT results are importantly inferior to Adenocard SPECT results.”

In other words, the available efficacy data do not verify sufficient similarity between CorVue and Adenocard such that the agents are diagnostically interchangeable. This interchangeability concept is important because the primary diagnostic efficacy outcomes in the CorVue Phase III studies were comparisons between the drug and Adenocard rather than a comparison between CorVue and a truth standard (coronary arteriography).

FDA’s specific concerns include the apparent inconsistencies among the Phase III study primary endpoint results; the appropriateness of the primary endpoint modifications initiated during the conduct of studies 302 and 305; the meaningfulness of the modified primary endpoint results; and the lack of a comparison arm within two of the Phase III studies that would have facilitated direct comparisons of the test-retest variability between CorVue and Adenocard.

The committee is asked to analyze the appropriateness of revising the primary endpoint success criteria and discuss the meaningfulness of the revised primary endpoint results. They must also compare those results to the meaningfulness of the original (unmodified) primary endpoint results.

FDA also wants to hear comments on the usefulness of the available coronary arteriography data, and of the data from the one study that included an Adenocard-retest arm.

Importantly, FDA may also request discussion of the need for any additional studies, either as pre-marketing or post-marketing expectations. The question appears to raise the possibility that King could walk out of the committee review with only an endorsement of post-marketing activities – essentially signaling a thumbs up for approval by the committee – despite its jumbled trials.

The Pink Sheet

“Alaven Rowasa Sampling Campaign Cited By FDA”

July 27, 2009

FDA’s Division of Drug Marketing, Advertising, and Communications doesn’t find anything jolly about Alaven Pharmaceutical’s holiday sampling campaign for Rowasa (mesalamine) Rectal Suspension Enema.

The 2008 Holiday Promotion Postcard reads: “Unwanted UC flares can make a surprise visit during the holidays. A change in diet and erratic stress levels may make flare symptoms worse. Make sure your patients are armed and ready with flare relief. Give them the gift of Rowasa Kit now. With a sample and a prescription of Rowasa Kit on hand, your patients are flare ready. They can enjoy the holidays (and so can you!).”

While the postcard presents various efficacy claims for Rowasa, it entirely omits risk information, including the warnings, precautions, and common adverse events associated with the drug, FDA’s warning letter, issued July 13, states.

“We acknowledge that the statement, ‘For Full Prescribing Information visit www.rowasakit.com’ is written in small type font at the bottom of the postcard. However, this does not mitigate the misleading omission of risk information,” DDMAC argued.

DDMAC said that the claims overstate the efficacy by implying that treatment with Rowasa will allow patients and their healthcare providers to “enjoy the holidays” by successfully treating all the various symptoms of flares from ulcerative colitis despite changes in stress and diet.

Rowasa is indicated for the treatment of active mild to moderate distal ulcerative colitis, proctosigmoiditis or proctitis, and is associated with several risks, including anaphylactic symptoms and acute intolerance syndrome.

While Rowasa has been shown to reduce patients’ disease activity index over several weeks, DDMAC acknowledged, the agency does not in any way support the implication that Rowasa will keep all symptoms under control during time periods like the holidays when flares are particularly likely to occur.

In addition, the statement, “With a sample and a prescription of Rowasa Kit on hand, your patients are flare ready,” suggests that Rowasa is useful in a broader range of conditions or patients than has been demonstrated.

“These claims misleadingly suggest that Rowasa is approved to treat any patient with ulcerative colitis,” wrote DDMAC. “However, it is indicated, among other conditions, for the treatment of active mild to moderate distal ulcerative colitis.”

The boilerplate enforcement language at the end of the letter illustrates the limitations inherent in FDA’s after-the-fact enforcement efforts: Alaven must immediately stop the distribution of the promotional materials, but if the firm is still using the campaign – which features a scowling gingerbread man – the FDA citation is probably a helpful reminder more than a burden.

Another aspect of the letter may create a burden for Rowasa. Because the citation is a warning letter, the company also must present FDA a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages.

“FDA’s DTC Review Problems Highlight Industry’s Growing Legal Squeeze”

July 27, 2009

The Government Accountability Office’s report on FDA’s staffing and budgeting problems highlights the agency’s funding challenge: it’s so strapped that it often can’t even effectively assess how it’s using its resources.

The drug industry understands this issue all too well, as anyone who has waited for a meeting with a review division, hoped for a guidance document to consult, or wondered when an application might get approved, can attest.

But the 1 GAO report, released July 20, highlights another challenge for industry: while many of the agency’s review and oversight functions will probably get attention from a safety-minded Congress and administration, one area that might not – resources for advertising pre-review – is becoming increasingly important to firms.

A number of recent legal settlements between firms and state attorneys general have resulted in requirements that companies receive pre-clearance of their direct-to-consumer advertising (”2 The ‘Super FDA’: State Attorneys General Flex Their Muscle in Pharma Enforcement,” The RPM Report, January 2009).

Indeed, Merck and Schering’s recent settlement with several states related to a failed study of Vytorin did not establish any new compliance terms, but it should drive home to industry that the existing terms which the firms affirmed – from prohibiting ghost writing to reducing conflicts of interest for data safety monitoring boards – should be seen as standard operating procedure if companies want to avoid legal trouble (3 ‘The Pink Sheet’ DAILY, July 15, 2009).

Among the terms is the requirement that the soon-to-merge companies obtain pre-approval from FDA for all DTC television advertisements and comply with agency suggestions to modify the ads. So FDA’s ability to quickly review DTC ads is paramount to anyone wanting to run a consumer campaign and stay on the right side of the law.

Industry had agreed to a user fee program for DTC ad review as part of the FDA Amendments Act of 2007, only to see the House Appropriations Committee block implementation (4 ‘The Pink Sheet,’ Jan. 21, 2008).

Even so, agency support for the examination of drug-related promotional materials has grown in recent years. Staff resources increased 26 percent from fiscal 2004 to 2008, going from 35 to 44 full-time equivalents, while funding jumped 167 percent, going from about $4 million to about $10 million, according to the GAO report.

FDA is still hiring advertising reviewers (5 ‘The Pink Sheet,’ July 6, 2009) but the staffing increase over those five years was outstripped by the growth in submissions of final materials, which increased 55 percent, and draft materials, which jumped 47 percent.

The number of draft submissions is tiny compared to the final submissions (2,709 versus nearly 300,000 between fiscal 2004 and 2008) but from a compliance perspective, these are ones that industry cares most about FDA reviewing, and that appears to be going down.

During the five-year period, FDA sent a total of 2,262 letters in response to its examination of draft promotional materials, down 44 percent.

“Although FDA officials noted that the agency did not have sufficient resources to examine all drug-related promotional materials submitted for review, FDA also could not provide information on the number of such materials staff reviewed,” GAO noted.

GAO has criticized FDA’s advertising reviews before, and in response to a report issued last year, the agency said that creating a tracking mechanism would take critical resources away from the reviews themselves (6 ‘The Pink Sheet,’ Dec. 18, 2008).

One bright spot for big pharma is that as it focuses more on specialty products, it may have better luck with advertising reviews. GAO found that the agency “did examine nearly all such materials for biologics.”

Overall, while GAO noted profound shortcomings in FDA’s ability to plan for its resource needs, it was generally satisfied with the approach the agency is taking to address the problems.

The agency pledged to “complete an inventory of all regulatory work products,” catalogued by center, and is also planning a broad staffing assessment – including most notably for its contractor workforce (7 ‘The Pink Sheet’ DAILY, July 21, 2009).

The Pink Sheet

“FDA Faults Cytogam Sales Literature For Unsubstantiated Long-Term Survival Claim”

July 23, 2009

An efficacy claim in sales literature cannot be based on a trend in a clinical trial, FDA informed CSL Behring in an untitled letter objecting to sales literature for the company’s Cytogam .

FDA questions several survival claims in a Slim Jim sales aid, including a statement that Cytogam (cytomegalovirus immune globulin intravenous, human) “was associated with increased 1-year and long-term survival of liver transplant recipients.”

A 1997 trial demonstrated increased one-year survival in liver transplant patients given CMVIG, notes the letter from CBER’s Office of Compliance and Biologics Quality. But although “there was a trend toward long term survival, the data for survival were not statistically significant beyond one year.”

FDA also objects to the following statements: “Significantly longer survival (79 percent survival at three years vs. 55 percent of those treated with ganciclovir alone,” and “Heart recipients: significantly greater 3-year survival and 3-year freedom from rejection.

A 2001 trial found a three-month improved survival rate for heart, heart-lung and lung transplant patients receiving CMVIG plus ganciclovir compared to those receiving ganciclovir alone, FDA says, but this was a preliminary cohort study using actuarial controls and multiple unadjusted endpoints.

Cytogam is indicated for prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas and heart. Labeling also says its use as a prophylactic should be considered in combination with ganciclovir when transplanting lung, liver, pancreas and heart from CMV seropositive donors into seronegative recipients.

The agency also objects to a claim that heart and lung transplant recipients receiving Cytogam had fewer deaths from obliterative bronchiolitis, noting that this condition is “not well-defined as having an association with CMV infections.”

A suggestion that Cytogam is efficacious for ganciclovir-resistant CMV disease is unsubstantiated, the agency adds, as is the suggestion that dual therapy is no riskier than ganciclovir alone.

Product labeling states that the addition of Cytogam to antiviral monotherapy, such as ganciclovir, “may expose the patient to toxicities and other risks associated with intravenous immune globulin therapy,” FDA points out.

CSL Behring acquired Cytogam from MedImmune in 2006 for an up-front payment of $50 million plus potential milestones. Launched in 1992, the biologic was MedImmune’s first commercial product.