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ANOTHER DAY, ANOTHER POLLING NADIR FOR OBAMACARE - This time, the bad news for the White House came from CBS, which found that 39 percent of respondents want the law wiped from the books, the highest percentage since the broadcaster began asking the question. That's compared to 36 percent who want to keep or expand the law. Recent polls have tended to show the law mired in continued uncertainty and unpopularity among Americans, a dynamic supporters hope will start to shift once the key benefits of the law come online in January.
Yesterday I had the privilege to chair the Clinical Trials Disclosure and Transparency Summit.
Here are my opening remarks:
Simplistic solutions to important public health issues are generally wrong, often deleterious to the issue at hand --and often hide political versus public health agendas. Or as Henry Kissinger once said:
”The real distinction is between those who adapt their purposes to reality and those who seek to mold reality in the light of their purposes.”
And so, with that introduction, welcome to the Clinical Trial Disclosure and Transparency Summit.
In a recent op-ed in the New York Times, biasedly titled, Health Care’s Trick Coin, Ben Goldacre (the author of the neutrally titled book, Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, made a number of serious allegations – and factual mistakes in his discussion of clinical trial transparency – specifically that the Clinicaltrials.gov registration requirement in FDAAA isn't being implemented and that only “full transparency and publication of clinical trial will address the issue.” It’s not so simple – and the facts matter.
As the former senior government official in charge of clinicaltrials.gov, it’s important to look at the facts – and the numbers.
In 2000, the National Institutes of Health (NIH) launched ClinicalTrials.gov to provide public access to information on clinical studies. Although it initially contained information primarily on NIH-funded research, it has been expanded to include both publicly and privately supported clinical research.
Since the launch of the site, it has been enhanced to significantly increase data sharing. The ClinicalTrials.gov database includes information on nearly 140,000 clinical trials in all 50 states and 182 countries.
Is anyone accessing this wealth of information? Yes! The NIH reported last year that ClinicalTrials.gov “receives more than 95 million page views per month and 60,000 unique visitors daily.
Facts do not cease to exist because they are ignored. Mr. Goldacre should realize that reality, although sometimes inconvenient to ones argument, remains reality.
As we progress through the next two days, here are some issues we will consider:
· The FDA is at the nexus of vast amounts of patient-level clinical data – what role will transparency play in making such information available? How might the agency accomplish such a task, how would it be funded – and where does such an initiative fall on the agency’s long list of urgent priorities?
· How will current AbbVie/Intermune legal decision in the EU impact transparency issues here at home?
· How will the IOM report impact how we view transparency going forward? Indeed – how will the IOM move forward on this issue – or will it?
· Should transparency be a government dictate or a working collaboration between interested parties both private and public – and what role should patients play. Should there be formalized transparency consortia? Should it be global?
· What are the implications for intellectual property and the connected question of incentivizing (or dis-incentivizing) investment in innovation? Is transparency a Trojan horse to attack patents and intellectual property rights?
· How can we avoid making transparency a game of “gotcha” such as what happened at the 2010 Avandia hearing where a grandstanding Henry Waxman pointed his finger at the GSK research chief and stridently said, “do you swear under oath that you will make all clinical trial data available? Only to get the embarrassing response, “Congressman, it’s available right now at www.gsk.com.”
· What about the availability of data from unpublished negative trials? Why aren’t payers asking for these before they make reimbursement decisions? For those of you following the debate over FDAMA 114 and the use of pharmaco-economic data for reimbursement decisions, this shouldn’t be an unfamiliar discussion. Can a free-market solutions drive transparency?
· Can transparency become a competitive advantage as well as a public health imperative?
After all, good things happen when everybody wins.
Ladies and Gentlemen – start your engines.
The Summit’s first speaker was Dr. Richard Moscicki, CDER’s new Deputy Director for Science Operations. His presentation focused on the transparency dichotomy of “the promise versus fear and loathing.”
As to “why” transparency, he offered reproducibility, re-analysis the potential to identify new information (placebo effects, biomarkers, endpoints, trial designs).
And then his talk got interesting. He laid it on the table that one group that is silently against transparency is academics – because they don’t want to be cornered into making studies public if it impacts their ability to publish.
The FDA’s impediments to data sharing, according to Moscicki are (1) Legal (data ownership, HIPAA/privacy, proprietary information), (2) technical/practical (format, data standards, CDISC, redaction), (3) Resources and, (4) the agency’s need to focus on its key mission.
Per that last point, he honestly shared that the FDA does not view (at least at as of right now) the issue of clinical trial data transparency as a key agency agenda item – unless there was move to move it to the head of the regulatory queue via user fees. (That would be DTUFA – Data Transparency User Fee Act. Folks – you heard it here first.)
But transparency is important and, per Moscicki, “inevitable” – and to that end he discussed the agency’s recent Federal Register Notice (Masked and De-identified Non-Summary Safety and Efficacy Data).
FDA invites comments on the issues it should consider with respect to the availability of clinical and pre-clinical study data after steps have been taken to “de-identify” it by removing any personally identifiable information and “mask” it by removing data that could link it to a specific application or sponsor. Specifically, the agency is interested in comments from the public on the following topics:
– What factors should be considered in masking study data (e.g. should certain data fields be removed or modified; number of different products to pool within a class)?
– Should there be any limitations on the agency’s ability to make masked data available?
– In addition to current FDA requirements to remove any names and other information that might identify patients, what other information should FDA consider when de-identifying the data?
– Would regulatory changes facilitate the implementation of this proposal?
– In what situations would disclosing masked data be most useful to advance public health?
Moscicki stressed that FDA’s approach has been under development for several years and
* It is not linked to EMA proposal;
* FDA is not contemplating routine preparation and release of de-identified and masked clinical and non-clinical study data;
* The agency is encouraging independently organized efforts to create, curate and share clinical trial datasets from all sources.
Dr. Moscicki’s complete PowerPoint presentation can be found here.
Next up on the agenda was Sir Alasdair Breckenridge, former Chairman of the MHRA and currently the Chair of United Kingdom’s Department of Health Emerging Science and Bioethics Advisory Committee.
Sir A. challenged the assemblage with the statement that transparency is “a process without a beginning or an end. It is a continuum.” And, “Transparency is like feeding a hungry dog – you more you give it, the more it wants.”
Cry havoc – and let slip the dogs of data transparency.
His presentation focused on four key questions:
(1) Should the public have access to data on which regulatory decisions are taken?
(2) What are the advantages and disadvantages of increased transparency?
(3) What are the key distinctions between transparency and communication (specifically the issue of public health literacy and numeracy – and the “road testing” of released information)?
(4) Will increased transparency lead to increased trust in regulators and industry?
On that last point, Dr. Breckenridge pointed out at increased transparency does not lead to increased trust. Trust depends on perceptions of honesty and competence, and transparency may expose inherent inefficiencies in a system. And that’s a good thing – if we really mean to make the most of transparency.
Transparency cannot be “for thee but not for me.”
He offered five keystones for moving forward:
(1) Agreement on timing of release of information
(2) Agreement on nature of information to be released
(3) Standards of protection of personalized data
(4) Standards for meta-analyses
(5) Rules of engagement for observational studies
He also discussed the EMA’s mad dash towards data transparency and the severe blow it was dealt by the legal victory of AbbVie and Intermune. A lesson that should be noted by the Ben Goldacres's of the world -- and the British Medical Journal.
Sir Alasdair’s PowerPoint presentation can be found here.
Maybe the FDA’s incremental and collaborative approach is best after all. Slow and steady ain’t sexy – but it generally works best -- and is in the best interest of the public health.
According to a report in the Pink Sheet, “Spurred by increasing stakeholder requests for clarity, FDA may be moving toward developing guidance on how and when drug firms can provide health care economic data to formulary managers.”
Per an FDA spokesperson “This is one of the areas that is of interest to FDA and we are discussing possible guidance development.”
The guidance could help clarify the regulatory parameters around the provision in the FDA Modernization Act of 1997 that allows drug companies to proactively disseminate health care economic information to formulary committees within certain limitations. Sec. 114 requires that such information be supported by “competent and reliable scientific evidence” and that any health economic information disseminated must “directly relate” to a drug’s approved indication.
As payers push for more information on the cost effectiveness of drug treatment, manufacturers are taking a closer look at Sec. 114 and are seeking direction from the agency on how it could be used. FDA Office of Prescription Drug Promotion Director Tom Abrams recently acknowledged heightened stakeholder interest in guidance on appropriate communications under FDAMA Sec. 114. “We know that’s a hot topic – what goes to formulary committees and similar bodies,” he said on June 25at the DIA annual meeting in Boston.
Abrams identified dissemination of health care economic information as one of four topics the agency is “exploring for future guidance development.” The other three are medical practice guidelines, comparative claims and “scientific exchange.”
Abrams’ DIA remarks are the first inkling of Agency movement since late 2011 when, according to a notice in the Federal Register:
The Food and Drug Administration (FDA) is announcing the establishment of a docket to assist with our evaluation of our policies on communications and activities related to off-label uses of marketed products, as well as communications and activities related to use of products that are not yet legally marketed for any use, we would like to obtain comments and information related to scientific exchange. FDA is interested in obtaining comments and information regarding scientific exchange about both unapproved new uses of products already legally marketed (“off-label” use) and use of products not yet legally marketed for any use.
And the issue of “scientific exchange” comes front and center. According to the FR notice, To assist with our evaluation of our policies on communications and activities related to off-label uses of marketed products, as well as communications and activities related to use of products that are not yet legally marketed for any use, we would like to obtain comments and information related to scientific exchange.
The FR notice puts this request into perspective:
On July 5, 2011, a citizen petition was submitted by Ropes & Gray and Sidley Austin LLP on behalf of seven product manufacturers (Petitioners): Allergan, Inc.; Eli Lilly and Co.; Johnson & Johnson; Novartis Pharmaceuticals Corp.; Novo Nordisk, Inc.; Pfizer, Inc.; and sanofi-aventis U.S. LLC under 21 CFR 10.30. The citizen petition requested that FDA clarify its policies for drug products and devices governing certain communications and activities related to off-label uses of marketed products and use of products that are not yet legally marketed for any use. Specifically, the petition requests clarification in the following areas:
1. Manufacturer responses to unsolicited requests;
2. Scientific exchange;
3. Interactions with formulary committees, payers, and similar entities; and
4. Dissemination of third-party clinical practice guidelines.
For some time, FDA has been considering these issues and is currently evaluating our policies on sponsor or investigator communications and activities related to off-label uses of marketed products and use of products that are not yet legally marketed for any use. We have been considering what actions to take in the areas specified by the petitioners with respect to manufacturer responses to unsolicited requests; interactions with formulary committees, payors, and similar entities; and the dissemination of third-party clinical practice guidelines.
Specifically, the FDA asks:
• How should FDA define scientific exchange?
• What types of activities fall under scientific exchange?
• What types of activities do not fall under scientific exchange?
• Are there particular types and quality of data that may indicate that an activity is, or is not, scientific exchange?
• In what types of forums does scientific exchange typically occur? Should the use of certain forums be given particular significance in determining whether an activity is scientific exchange or an activity that promotes the drug or device? If so, which forums?
• What are the distinctions between scientific exchange and promotion? What are the boundaries between scientific exchange and promotion?
• Generally, who are the speakers involved in scientific exchange, and who is the audience for their communications?
• Should the identity of the participants (either speakers or audience) be given particular significance in determining whether an activity is scientific exchange or an activity that promotes the drug or device? If so, which participants would be indicative of scientific exchange and which would be indicative of promotion?
• How do companies generally separate scientific roles and promotional roles within their corporate structures?
• How should the Agency treat scientific exchange concerning off-label uses of already approved drugs and new uses of legally marketed devices? Please address whether there should be any distinctions between communications regarding uses under FDA-regulated investigation (to support potential approval) and communications regarding uses that are not under express FDA-regulated investigation.
• How should the Agency treat scientific exchange concerning use of products that are not yet legally marketed (that is, products that cannot be legally distributed for any use outside of an FDA- or institutional review board (IRB)-approved clinical trial)?
• Should investigational new drugs and investigational devices be treated the same with respect to scientific exchange? Why or why not?
• Under 21 CFR 812.7(b), an investigational device is considered to be “commercialized” if the price charged for it is more than is necessary to recover the costs of manufacture, research, development, and handling. Similarly, FDA considers charging a price for an investigational drug that exceeds that permitted under its regulations (generally limited to cost recovery) to constitute “commercialization” of the drug (see 74 FR 40872 at 40890, August 13, 2009; 52 FR 19466 at 19467). What other actions indicate the commercialization of drug and/or device products? If there are differences in the steps taken to commercialize drug products and the steps taken to commercialize device products, either before or after approval, please explain these differences.
A lot of questions and, it seems, a lot of potential regulatory mission creep.
Relative to, “Interactions with formulary committees, payors, and similar entities,” the door is now also open for debate on FDAMA Section 114 and health economic data.
There is no on-the-books draft or final guidance on Section 114. It’s been 14 years since the initial language. Health-related quality of life claims are considered under the established "adequate and well-controlled trials" standard.
Some background to put this into perspective:
To address concerns that FDA regulations were limiting the dissemination of outcomes research, Congress added Section 114 to set a new, less stringent standard applicable to promotional dissemination of health care economic information to MCO formulary committees: "competent and reliable scientific evidence."
Even though there is no FDA guidance to explain the agency's understanding "competent and reliable scientific evidence,” PhRMA developed a draft guidance, which was submitted to the FDA in June 1998. In its draft, PhRMA sought input from the International Society for Pharmacoeconomics and Outcomes Research, the Society for Medical Decision Making, the Academy of Managed Care Pharmacy, the American Pharmaceutical Association, and other groups.
In its submission to the FDA, PhRMA explained the history behind Section 114 and proposed guidance on the following terms used in the new law:
- Health care economic information.
- Managed care or other similar organizations.
- Formulary committee or other similar entity.
- Directly related to an approved indication.
- Competent and reliable scientific evidence.
The PhRMA proposal took an approach to interpretation consistent with Congress's intent that Section 114 would increase the dissemination of outcomes research information by product manufacturers to MCOs. PhRMA concluded that the term "health care economic information" should include all forms of economic analysis so the guidance could adapt to new and evolving outcomes research methods.
One of the phrases in Section 114 that is difficult to interpret is that promotion must involve a claim that "directly relates to an indication approved [by the FDA]." In the draft guidance, PhRMA proposed that extrapolation from data included on labeling would be appropriate at least under the following circumstances: from duration of use in labeling to actual duration of use found in pharmacy databases, from dosages included in labeling to actual dosages found in pharmacy databases, and from controlled trial settings to actual practice settings.
The standard set by Section 114, "competent and reliable scientific evidence," is the same standard used by the Federal Trade Commission (FTC) when assessing the adequacy of substantiation for manufacturer claims involving OTC drugs and products affecting environmental health. That standard requires transparency of methods and use of methods accepted by experts in the field. In its proposal, PhRMA recommended that the FDA follow long-established FTC interpretation of the competent and reliable scientific evidence standard.
The full FR Notice on "Communications and Activities Related to Off-Label Uses of Marketed Products and Use of Products Not Yet Legally Marketed; Request for Information and Comments" can be found here.
In October 2012, PhRMA issued a white paper, asking the FDA for guidance on the supporting evidence drug companies need for the health care economic data they send to formulary managers should specifically allow for use of a range of data sources, not limited to adequate and well-controlled clinical trials.
The white paper urges the agency to develop formal regulatory guidance on Sec. 114 of the FDA Modernization Act of 1997, which allows drug companies to proactively disseminate health care economic information to formulary committees within certain limitations.
The white paper outlines a number of data elements that should satisfy the competent and reliable scientific evidence standard. They include: methods for establishing economic costs and consequences that are widely accepted by experts in the field using a clear, pre-defined study protocol; an “accurate and balanced assessment of the economic consequences of a drug therapy, consistent with the current weight of credible evidence”; a representative study population; and information that allows the reader to determine how the research was conducted.
PhRMA recommends that FDA allow the competent and reliable standard to be satisfied with data obtained through a number of different methods, including observational study designs, database reviews and other economic modeling techniques. “There should be no pre-specified number or type of study required to substantiate a claim."
For example, “a claim that a drug is more cost-effective than a competing drug may be made where the cost savings are due to reduced resource utilization resulting from improved efficacy outcomes, decreased administration or monitoring costs, or where the difference in cost is due to the drug causing fewer adverse events, as long as these differences are supported by competent and reliable evidence.”
PhRMA argues that FDA should not consider such a statement a comparative clinical claim, which would trigger the “substantial evidence” requirement involving clinical trials.
Companies should be permitted to disseminate data on the “real world” economic implications of a therapy on health outcomes, according to the white paper. For example, “if a manufacturer conducts a competent and reliable study investigating the impact of a drug indicated for the treatment of diabetes mellitus on costs associated with cardiovascular care, the manufacturer should be permitted to proactively disseminate such data to appropriate audiences.”
Tom Abrams’ comments should act as more than a passing notice. Folks – it’s time to step up to the plate – the implications for payers and academic detailing are both timely and significant.
From that well-know Tea Party mouthpiece – the Associated Press …
FACT CHECK: Obama spins health insurance rebates
WASHINGTON (AP) - Another year, another round of exaggeration from President Barack Obama and his administration about health insurance rebates.
In his speech defending his health care law Thursday, Obama said rebates averaging $100 are coming from insurance companies to 8.5 million Americans. In fact, most of the money is going straight to employers who provide health insurance, not to their workers, who benefit indirectly.
Obama danced around that reality in remarks that also blamed problems in establishing affordable insurance markets on political opponents, glossing over complex obstacles also faced in states that support the law.
A look at some of his claims and how they compare with the facts:
-"Last year, millions of Americans opened letters from their insurance companies. But instead of the usual dread that comes from getting a bill, they were pleasantly surprised with a check. In 2012, 13 million rebates went out, in all 50 states. Another 8.5 (million) rebates are being sent out this summer, averaging around 100 bucks each."
- After introducing several people who got rebate checks last year: "And this is happening all across the country. And it's happening because of the Affordable Care Act. Hasn't been reported on a lot. I bet if you took a poll, most folks wouldn't know when that check comes in that this was because of Obamacare that they got this extra money in their pockets. But that's what's happening."
-" If they're (insurers) not spending your premium dollars on your health care - at least 80 percent of it - they've got to give you some money back."
THE FACTS: Just as he did a year ago, Obama made a splashy announcement about rebates that incorporates misleading advertising.
The health care law requires insurance companies that spend too much on administrative expenses to issue rebates to customers. But those customers are often employers that in turn offer insurance to workers and bear the bulk of the costs. In workplace plans, the rebate goes to the employer, which must use it for the company health plan but does not have to pass all or part of it on to the worker. People who buy their own insurance and qualify for a rebate get it directly.
Obama was on solid ground in saying "millions of Americans" got rebate checks last year, but the number was not close to 13 million as he implied.
Of the 12.8 million rebates announced last year, health policy experts estimated 3 million would go directly to the insured. The government didn't know how many.
Nearly two-thirds of the 12.8 million were only entitled to pro-rated and decidedly modest rebates, because they were covered by employers that pay most of their premiums. Workers typically pay about 20 percent of the premium for single coverage, 30 percent for a family plan. Employers pay the rest.
And employers can use all the rebate money, including the workers' share, to benefit the company health plan, perhaps restraining premiums a bit or otherwise improving the bottom line. The law requires insurers to spend at least 80 percent of premiums they collect on medical care and quality improvement, or return the difference to consumers and employers.
Altogether, this year's rebates are worth $500 million, down from $1.1 billion returned last year. The government says the lower rebates mean insurance companies are becoming more efficient.
-"I'm curious, what do opponents of this law think the folks here today should do with the money they were reimbursed? Should they send it back to the insurance companies?"
THE FACTS: Even in that unlikely event, most people could not send it back to insurance companies because the money doesn't go "in their pockets" and they have no control over what their employers do with it.
-"In states that are working hard to make sure this law delivers for their people, what we're seeing is that consumers are getting a hint of how much money they're potentially going to save because of this law. In states like California, Oregon, Washington, new competition, new choices, market forces are pushing costs down."
THE FACTS: It is simply not known whether health insurance will become less expensive in those states - or nationally than it is now, or than it would have been absent the law. And hitches in setting up the new insurance marketplaces called exchanges are not limited to Republican-led states where leaders object to the law, although that political pushback is certainly part of what's going on.
In California, for example, where there is plenty of competition by health insurers wanting to get into the exchange, an actuarial report commissioned by Covered California, the state agency running the insurance marketplace, found that middle-income residents could see individual health premiums increase by an average of 30 percent while costs go down for lower income people.
In West Virginia, Democratic Gov. Earl Ray Tomblin - also a cooperative partner in expanding Medicaid and setting up an exchange - complained to federal officials this week about delays in rules and guidelines from Washington as the state struggles to meet deadlines under the law.
"Many West Virginia families have expressed frustration" trying to find out how much policies from the exchange will cost them and whether they will get a subsidy, he said, and the state is "dangerously close" to falling short of requirements under the law.
In case you had any doubt that Indian policy on pharmaceuticals isn’t predicated on domestic manufacturing policy …
A day after a high-level panel headed by Prime Minister Manmohan Singh relaxed foreign direct investment (FDI) norms in sectors ranging from telecom to single brand retail, he’ll be holding a separate meeting to review the policy in the pharmaceutical sector.
According to a senior official, "The main concern of the Ministry of Commerce and Industry is that a stage might come when India might not have a company ready to manufacture drugs on behalf of the government, even if the provision of compulsory license is invoked.”
Shouldn’t the fact that acquiring companies are paying huge valuations -- many time the cost of setting up new projects -- raise a question as to their motivation – and that of the Indian government?
Another example of domestic manufacturing policy trumping the public health?
It took only two months after patent expiry in China for two generic versions of Novartis AG’s blockbuster chronic myeloid leukemia drug Glivec (imatinib) (marketed as Gleevec in the U.S.) to gain China FDA approval, and many more are expected to follow suit. But Novartis plans to fight back by highlighting the quality and efficacy of its brand and its long-running patient assistance program.
Two companies received CFDA approval June 26, Jiangsu Hansoh Pharmaceutical Co. Ltd. and Jiangsu Chia-tai Tianqing Pharmaceutical Co. Ltd., or CTTQ, 60% of which is held by Hong Kong-listed Sino Biopharmaceutical Ltd. CTTQ holds the first capsule generic approval, while Hansoh received CFDA approval for a tablet formulation of imatinib. Generic imatinib for chronic myeloid leukemia will launch in August, Sino Biopharmaceutical said during a July 4 event.
Although the Glivec compound patent expired in China in April, Novartis still holds a beta crystalline patent in the country until 2018 and a patent for a gastrointestinal stromal tumors indication until 2021, Novartis China said. According to Novartis, the two China generics are likely alpha crystalline forms of imatinib.
“The generic has a different crystal type, so the product quality and treatment result will be totally different,” said Wendy Wang, head of communications for Novartis Oncology China.
The imatinib generics race is just warming up. According to CFDA’s database, as of July 16, there were 16 new applications for imatinib generics in 2013, including an imported drug application.
For those of you following the recent CMS decision to deny coverage for contrast-enhanced PET scans ("Taking CMS to the Wood CED"), BioCentury’s Steve Usdin offers a timely and granular peek into the related world of laboratory-developed molecular diagnostics, detailing the cost, time and risk required to get these basic tools of personalized medicine onto the market -- and the decreasing the certainty that they will be covered.
Some snippets:
The cost of demonstrating clinical utility, along with the lack of clear or consistent standards, is killing a business model that had made it possible for small companies to commercialize molecular diagnostics quickly and cheaply.
The fate of these laboratory-developed molecular diagnostics companies, and especially the conclusions investors draw about the viability of the space, could shape the future of personalized medicine.
Labs have been sparring with FDA for at least a decade over the agency’s attempts to regulate LDTs, and so far they’ve kept the regulators at bay. FDA Commissioner Margaret Hamburg opened the latest front at the American
Society of Clinical Oncology meeting in June, when she announced the agency plans to eliminate the regulatory distinction between LDTs and in vitro diagnostics marketed to multiple labs or physicians that have long been subject to premarket review.
The agency has developed a draft guidance that would “regulate all in vitro diagnostic tests in the same risk-based framework the agency currently uses, whether or not they are performed by a single laboratory.”
While FDA will find it difficult to use guidance documents or rules to impose clinical utility requirements on LDTs, payers have found a more prosaic tool for achieving the same goal: billing codes.
The full BioCentury article, “Coding for Utility,” can be found here.
Why is it that, when the pharma industry does things right, the story goes unreported in the mainstream media?
That’s a rhetorical question.
Here’s the good news:
Per a new study by Johns Hopkins University (and supported by AHRQ), FDA requirements for postmarket data on new prescription drug approvals have raised the number of postmarket studies completed and reduced the number of uninitiated studies by manufacturers.
Following the passage of the Food and Drug Administration Amendments Act (FDAAA) in 2007, the number of completed studies that fulfilled postmarket obligations nearly doubled from 6.6% in 2007 to 12.6% in 2011.
Among studies not yet initiated by the manufacturer, there was an opposite trend over the study time period, with 56.7% studies not started in 2007 and 43.5% not yet started in 2011, they wrote in a research letter online in the Journal of the American Medical Association.
"Our analysis found the number of studies not yet started declined during this 5-year period, and the number of studies fulfilling obligations nearly doubled," the authors pointed out.
Prior to 2007, drug manufacturers completed postmarket safety trials on a voluntary basis. The passage of the FDAAA authorized the agency to require manufacturers to submit postmarket data as part of the prescription drug approvals process, as well as holding manufacturers to deadlines.
Many rare, but potentially serious adverse events are only found after a drug receives FDA approval, the authors noted.
The study reviewed changes in fulfillment of postmarket studies following the passage of the FDAAA from 2007 to 2011 through a review of all postmarket study status data for both biological and new drug applications.
Studies were categorized as pending, ongoing, delayed, terminated, submitted, released, and fulfilled.
The total number of postmarketing studies in each year in the study period was greater than the number required under the act:
- 1,841 versus 0 required in 2007
- 1,901 versus 46 in 2008
- 2,227 versus 153 in 2009
- 1,774 versus 279 in 2010
- 1,781 versus 387 in 2011
The authors noted three trends over that time: the number of studies not yet started decreased, completed studies that met postmarket requirements increased, and delayed studies also increased. The number of studies not yet started fell from 1,044 (56.7% of all studies) in 2007 to 775 (43.5%) in 2011. Completed studies rose from 122 (6.6%) in 2007 to 224 (12.6%) in 2011. Delayed studies rose from 125 (6.8%) in 2007 to 241 (13.5%) in 2011.
Over the study period, the number of ongoing studies, studies submitted for FDA evaluation, and terminated studies remained relatively constant.
"These trends help address concerns expressed by the Institute of Medicine that many postmarketing studies before the FDAAA were not implemented or fulfilled," they wrote, cautioning that in spite of improvements, "more than 40% of studies had not yet been started in 2011," while the number of studies that were delayed doubled over the study period to "approximately one in eight."
The authors also noted that their research was limited by a design that did not statistically isolate the legislation's effect on fulfillment rates, and a lack of examination of content and outcomes of postmarketing studies.
From the pages of Drug Industry Daily …
China Investigating Drug Pricing At Domestic, Multinational Firms
The Chinese government is conducting a review of drug pricing and manufacturing costs at selected domestic and international companies, with an eye on making healthcare more accessible to its people.
The review, by the National Development and Reform Commission (NDRC), will look at drugmakers’ data from 2010 through 2012, including corporate audit reports, sales agreements and shipping records. Importers will also be asked to provide information about border control costs such as customs clearance, quarantine fees and storage fees, a July 2 NDRC notice says.
According to Citi Investment Research analyst Richard Yeh, the inquiry will target about 60 drugmakers — including GlaxoSmithKline, Boehringer Ingelheim, Fresenius Kabi and Sandoz — and focus on prices of drugs recently added to the 2013 essential medicines list and preferentially priced branded generics from multinationals.
“Our checks also suggest that the survey may not necessarily lead to price cuts on the surveyed drugs or imply another round of price cuts, but likely reflects the NDRC’s intention to build a more optimized drug pricing regulation system and to provide a basis for future price cuts” on exorbitantly priced drugs, Yeh writes in a research note.
Helen Chen, head of L.E.K. Consulting’s China life sciences practice, said the exercise could be useful if the NDRC’s aim is to educate itself about the cost of providing quality drugs.
“The key issue here, though, is whether they understand the cost of drug quality goes beyond the simple manufacturing [cost of goods sold],” Chen said. “I hope NDRC’s intention is not just tallying ex-factory price and mandate [sic] a small allowable markup as they had proposed for device manufacturers.”
Peter Pitts, president of the Center for Medicine in the Public Interest and a former FDA associate commissioner, also sounded a note of skepticism. “It’s important for Beijing to understand and appreciate that lower cost does not necessarily lead to broader patient access,” he told DID Wednesday. “For example, the 100 top drugs on the World Health Organization’s essential drug list are all off-patent and yet there is still little or no access to them in China.”
Also of concern, Pitts added, is that the national government’s control over manufacturing issues in the provinces has proven to be spotty, despite recent regulatory advances at the ministry level.
The survey comes amid an ongoing effort by China to “establish a healthcare system covering urban and rural residents, and to provide safe, effective, convenient and affordable medical service,” as explained by then-President Hu Jintao in 2007.
Chen noted that, in the early 2000s, the government had to force 10 large drugmakers to produce a list of basic medicines that companies had stopped making because the prices were too low to be profitable. According to Yeh, the NDRC released a guideline for drug ex-factory price surveys in November 2011 and began creating a mandatory ex-factory drug price reporting system in September of last year.
Pfizer has received European approval to expand the use of its pneumococcal conjugate vaccine Prevenar 13 to adults aged 18 to 49 years for the prevention of invasive pneumococcal disease, according to a company statement.
The vaccine, which protects against 13 strains of Streptococcus pneumoniae, is approved in the European Union (EU), the United States, and elsewhere for use in infants, young children, and adolescents aged 6 weeks to 17 years, as well as adults 50 years of age and older.
"Prevenar 13 is now the only pneumococcal vaccine in the EU that offers protection against invasive disease from infancy through adulthood." the company said in the statement.
The European Commission's decision to expand use of the vaccine to 18- to 49-year-olds followed the submission and review of data from an open-label phase 3 trial of the vaccine in healthy adults in this age group, the company said.
The study, which met all primary and secondary objectives, showed that the vaccine is at least as immunogenic in this age group as it is in adults aged 60 to 64 years, as measured 1 month after vaccination. Prevenar 13 showed a favorable safety profile and was generally well-tolerated.
"Adults aged 18 to 49 years with certain underlying medical conditions may benefit in particular from vaccination with Prevenar 13 because of an increased risk of pneumococcal disease," said Luis Jodar, PhD, vice president of the Vaccines Global Medicines Development Group at Pfizer.
Prevenar 13 (known as Prevnar 13 in the United States, Canada, and Taiwan) is now approved in more than 120 countries worldwide for use in infants and young children, as well as in more than 80 countries for use in adults 50 years of age and older.
But not approved for scheduling in the United States (beyond patients who are immunocompromised or over age 65). What’s wrong with this picture?
On the last working day of the year (December 30, 2011), the FDA approved Prevnar 13 (a pneumococcal 13-valent conjugate vaccine) for people ages 50 years and older to prevent pneumonia and invasive disease caused by the bacterium, Streptococcus pneumoniae. In fact, the new use for Prevnar 13 was approved under the agency’s accelerated approval pathway, which allows for earlier approval of treatments for serious and life-threatening illnesses.
(The Centers for Disease Control and Prevention reports that 5,000 adults die from pneumonia every year.)
And to drive home the importance of this action, the FDA issued a press statement on the approval before heading home for the long weekend:
“According to recent information for the United States, it is estimated that approximately 300,000 adults 50 years of age and older are hospitalized yearly because of pneumococcal pneumonia,” said Karen Midthun, M.D., director of FDA’s Center for Biologics Evaluation and Research. “Pneumococcal disease is a substantial cause of illness and death. Today’s approval provides an additional vaccine for preventing pneumococcal pneumonia and invasive disease in this age group.”
Not so fast.
Although it’s quite a high hurdle to have a vaccine approved by the FDA (and appropriately so), it’s not the final hurdle in getting it to patients. That final hurdle resides with the Centers for Disease Control’s Advisory Committee on Immunization Practices (ACIP).
ACIP’s charge is to “provide advice and guidance to the Secretary, HHS, the Assistant Secretary for Health, and the Director, CDC, regarding the most appropriate selection of vaccines and related agents for effective control of vaccine-preventable diseases in the civilian population.”
The ACIP meets three times a year, and during these meetings newly licensed vaccines are discussed and a vote is taken to include (or not include) the new vaccine on the adult immunization schedule. ACIP’s recommendations become a basis for reimbursement by public and private payers who will pay for vaccinations that are part of the committee’s recommendation -- but generally not otherwise. The CDC schedule plays an important gatekeeper role for vaccines that goes well beyond the scope of FDA approval. Vaccines approved by the FDA but not appearing on the CDC routine vaccination schedule are likely to gain little traction because of a lack of guidance to providers on how to use the vaccine -- and lack of payer coverage.
In other words, minus a positive ACIP recommendation, a disease that is responsible for approximately 200,000 emergency room visits a year will continue to harass patients and haunt our healthcare system. Minus a positive ACIP vote, new and potentially life-saving vaccines are redlined and another nail is hammered into the coffin of innovation.
The need for this patient population exists. The vaccine is safe and effective. Without a recommendation the vaccine will not be available to a large swath of Americans. It’s time for ACIP to call the question.
The battle against the “dangerous idiots” of vaccine denial is dangerous enough, we must avoid the equally daunting danger of … inertia
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
