Abram’s comments, made during a panel this morning at the Drug Information Association’s (DIA) annual meeting in Chicago, prompted audience members to probe Abrams, and his CBER colleague Lisa Stockbridge, branch chief of the Advertising and Promotional Labeling Branch, about specific policies governing online promotion. One audience member wondered whether unbranded, educational campaigns online could link to branded sites, or if that kind of activity would generate an enforcement letter. Abrams responded that his own question, in that instance, would be, “Why are you linking to a brand site?” if a campaign is designed specifically to educate about a disease, as opposed to a branded campaign designed to sell a product. When pressed, he said an educational or awareness campaign – which isn’t required to present risk information, since no drug is being promoted – linking to a brand site would “have to be considered on a case by case basis.” Industry has been browbeating DDMAC about issuing social media guidelines for years.

On FDA’s Bad Ad program, one audience member asked what sort of proof would be required to verify improper promotion by a sales rep, given that a discussion between a rep and a physician would likely be verbal and unrecorded. Abrams said that an extensive review of the complaint would happen before moving forward, and then a signed affidavit from the physician, testifying to what was said during a sales meeting, would most likely be required. John Kamp, executive director at the Coalition for Healthcare Communications, and moderator of the panel, wondered aloud about whether a sales rep making hundreds of calls a week would be able to recall exactly what was said during a specific detail. “Couldn’t a sales rep say, ‘I don’t remember what I said, but my training and common response in this situation would be X.’ Would that kind of [defense] fly?” asked Kamp. Abrams didn’t answer the question directly, but insisted that DDMAC was diligent in investigating complaints, and the circumstances surrounding a potentially illicit conversation.

Abrams also discussed a proposed update to Section 502(n) of the Federal Food Drug and Cosmetic Act (FDCA) dealing with “clear, conspicuous, and neutral” major statements, or legally-mandated statements on major risks associated with a given drug. The update was announced in March of last year, and deals with DTC advertising, specifically television and radio, said Abrams. One of the four proposals put forward by DDMAC would require that an “advertisement does not include distracting representations (including statements, text, images, or sounds or any combination thereof) that detract from the communication of a major statement.” Anyone who has seen a drug ad on television will recognize the target of this proposal; the last seconds of a DTC ad are typically used for a voiceover announcing a drug’s “major” risks, while simultaneously providing unrelated images associated with the actors or visual narrative of the commercial.

DDMAC is in the process of being elevated from a division to an office, a process that is “slow even by government standards,” joked Abrams. The new office will be separated into two divisions, healthcare professional and consumer, he said.

The latter question was posed to Kevin Duffin, senior fellow, translational sciences at Eli Lilly – and a Six Sigma practitioner – at the conclusion of a Drug Information Association (DIA) panel on Monday. During the panel, Duffin unveiled a formula he uses at Lilly to “apply industry probabilities to drug design,” the goal being to increase commercial potential, while reducing costs and shorting cycle times in the early stages of drug discovery.

The particular equation that Duffin suggested had to do with locating a “sweet spot” based on the ratio between a compound’s molecular weight (which correlates with bioavailability, he said), and its lipophilicity, or ability to dissolve in fatty oil. Too much molecular lipophilicity affects the proteins in water, leading to potential off-target responses, said Duffin.

The current industry trend, per Duffin, is the heavier the molecular weight, the higher its lipophilicity. While the “IP police” wouldn’t let Duffin discuss particular Lilly compounds, he said the company falls in line with the trend. For Duffin, the proper ratio for locating the sweet spot is a molecular weight less than 400, and a lipophilicity measure (known as ClogP) of less than three, combined with several other “desirable guidelines.” In response to the question of whether this kind of criteria-setting inhibits creativity in the lab, Duffin said “some love it and some hate it,” adding that Lilly CEO John Lechleiter “is embracing Six Sigma” as a tool to make the discovery process more efficient. The financial benefit of the sweet spot ratio has already saved Lilly upwards of $7.3 million, and has upped the chances of a given drug’s approval by 2%. If that doesn’t seem like much, consider that fact that the average drug candidate has only a 10% chance of approval, according to Duffin.

Michael Walega, a Six Sigma Master Black Belt at Covance, a CRO, said all parts of his company, “from preclinical through phase 4,” are steeped in the ways of Six Sigma. He called for a reevaluation of organizational culture in industry, based on four steps: awareness, motivation, competency, and implementation.

Michael Naimoli

In the past few years, Microsoft has been working hard to create clinical trial platforms for the pharmaceutical industry. This year, the Redmond, WA-based behemoth has moved full-speed ahead with its virtual-server system, dubbed Azure.

Microsoft is not only working on hosted applications, instead the company has established a massive online server or “cloud” that forms the backbone for online software providers (in-house pharma or third party) to host their programs on. Pharm Exec sat down with Microsoft’s National Director, US Life Sciences Michael Naimoli to find out if pharma is ready to move its software from the back room to the cloud.

Is cloud computing catching on with pharma customers?

Pharma companies are very interested in the technology. Right now, I can’t mention their names or what they are doing, but much of it centers around high-performance computing. The fact that Azure is an expandable fabric that allows a company to spin up servers as needed and spin them down when not, allows companies to pay for compute time as they need it rather than maintain their own servers.

Azure is your cloud, but do you have plans to create applications that can sit on the cloud?

We want pharma companies to put their own applications on Azure, because it is a platform for developers. What’s nice about it is that there can be a migration from on-premise to off-premise in terms of the applications. Thinking pharma specific, all the products that these companies develop are essentially data–it’s not like manufacturing chairs. You must be able to converse and make sense around the data. A service that allows people to put data on it and then have applications there to have the sense making opens up all sorts of possibilities with respect to pipeline and portfolio management.

So who is your customer, the pharma companies or the software developers?

There are software vendors that we would like to see move their software onto our platform–that would be ideal. But we are also looking to enable the developers in pharma as well. It’s a little bit of both.

Can you give me an example how a pharma company can move one of their in-house software platform to the cloud?

Look at all the data that goes into protein folding. Companies that are developing large molecule products–usually they are called monoclonal antibodies. The activity of that molecule is bound up in how it folds itself. During the discovery process they like to look at the primary sequence of that product and they want to do calculations about how it’s going to fold. They have traditionally maintained a large number of CPUs that have to be spun up around that activity and it can take 70 hours to finish up the whole protein folding analysis. With a cloud-based utility model, the servers don’t have to be on all the time, Something like that, that you don’t do all the time, scientists can work with the data when they need to, and the servers don’t have to be spinning when they are not needed.

How does compliance work? If the software is already compliant, does that mean Azure is too?

Ultimately it is up to the sponsor to decide if it is a validated application. It depends on what the server is being used for.

Microsoft sells a clinical software (Amalga). Are there plans to make that a hosted application?

I can’t speak to that. As far as I know there are no plans to make a cloud version of Amalga.

Are companies forced to stay online when they move their software to a cloud-based system?

The customers get to pick and choose what commodity applications they want to host in the cloud and if they want to move some applications to the cloud today and others tomorrow they are able to. They can do a combination of on-premise and off-premise. That’s the big competitive difference with a Google where software is all or nothing in the cloud.

Pharma is notoriously nervous about new technology. Has there been a huge buy-in so far or are companies simply dipping their toes in the water? Is it hard to get pharma to jump into SaaS?

Pharma is in the same area that a lot of other industries are. They are willing to take the risk when you are talking about business functions and applications that aren’t mission critical to pharma. I think we are definitely going to be in a place, in the not too distant future where you are going to see companies take their portfolio of products and pushing them up to a data exchange and sharing that information out. They can’t get to all the work, and a risk profile for one company is different from a risk profile from another company so they might want to push that information up and have other companies look at it.

If they want to in-license it, they can do the work around the data rather than hirer teams of people to move the data over. I think that we are coming to a situation where R&D will be collaborative in the cloud and the cloud is going to host data around all products and development and in the end the world will have access to pharmaceutical products to develop and ultimately get market because they won’t have to wait for someone to discover it in their data center because they don’t have time.

Janet Woodcock

While the convention floor of the 46th annual meeting of the Drug Information Association bustled with the usual vendors touting the latest and greatest clinical trial technology, the panels (particularly those that featured FDA members) had a remarkably somber tone.

The main refrain was: “Things are going to change and everyone must step up or get trampled.” However, those comments were often followed by: “We are going to have to change, but we have no idea how or how much it will cost.”

“Drug development is in crisis, and there is a demand for better evidence,” said Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research during her panel presentation “The Impact of New Comparative Effective Requirements.”

“Right now, we are at the same point with comparative effectiveness as we were with drug efficacy in 1960,” Woodcock said. “We didn’t know how to do it, and there was a lot of resistance to it. There was a battle over efficacy that almost died.

“In 2010 there is no requirement for comparative evaluation pre-market,” Woodcock continued. “Effectiveness is something different. Pre-market  clinical trials won’t give you that effectiveness, because they aren’t done in a ‘real world’ setting. The preferred methodologies we don’t actually know. There are people out there that think we can just push a button on healthcare data sets and get the answers.”

She also noted that pharmaceuticals, unlike other health technologies, have a tremendous evidence base. “The FDA Amendments Act explicitly calls for additional evidence regarding safety when new safety questions come up after marketing,” she said. “Comparative effectiveness is a call for more outcomes data to guide practice. It’s a trajectory that industry must recognize. This is where we are all going together.”

She pointed out that there are budgetary restraints in government so it will fall into pharma’s lap to perform these new pre and post market trials. “Unfortunately, right now, drug development is in crisis, but this isn’t a good time for the pharma industry to take on new requirements,” Woodcock said. “For the regulators, this is a huge problem. Drug regulators are caught between two societal expectations and demands. On one hand you have the rising desire for certainty, and on the other they want innovative drugs.”

In Europe, they think that the tech assessors such as NICE are going to start planning pre-market, during the drug development process, and give advice on how to fulfill the technology assessors requirements. In that way, the drug development process can be seen as a seamless process that takes care of the regulators needs as well as the payer’s needs.

The Tough Questions
“The problem that we have is that we had 50 years of experience working this out,” Woodcock said. “The technology assessors don’t think the same way regulators do—we have a great deal more experience in trial methodology and analysis. We realize the limitations in data and the methodology in CE has not been worked out.”

She said that there will be tremendous pressure on industry and regulators for more evidence and that’s what’s driving the controversy about safety. The question is: Who in the US will generate this initial evidence, and what evidentiary standards will be applied? FDA just opened a study with the Institute of Medicine on the use of observational studies and other types of databases versus randomized control trials to evaluate safety signals.

Woodcock brought up two more questions: How will the standards be implemented and when in the drug development product should what evidence be generated? How much certainty should we have in any given point during drug development?

“It’s imperative that the United States develop a clinical trial infrastructure,” Woodcock said. “We don’t have a machine to generate all this evidence. We don’t have any mechanisms in place to generate all this evidence. It’s time that we develop the capacity to find out these answers in a way that doesn’t cost hundreds of millions of dollars every time we ask a question.”

The Harder Answers
For certain diseases, like cancer, the answers might be driven from the patient side. The Cystic Fibrosis Foundation has set up such a network for their patients so they can get into trials for new treatments rapidly—and so that those new treatments can rapidly be evaluated.

Another suggestion Woodcock offered is to move on the science of new personalized medicine. “That’s the best way to improve the value of medicine,” Woodcock said. “We must target it towards populations that stand to benefit more and don’t have as much risk. We are there on the science.”

Finally, she said that there’s new science of safety evolving and that has to do with Sentinel and the use of electronic health records. That science will help industry and FDA evaluate the performance of medical products once they are released. “The problem is that the science is also in its infancy, and there are a large number of questions that we’ll have to answer before those types of databases can be used to answer the questions we have about outcomes,” Woodcock said. “Comparative outcomes data are essential for evidence-based medical practice, and they have to be gathered in real world settings so in some ways the premarket world is not the time to get this information. Methodologies for doing this kind of research in the US are lacking. Work is ongoing, but more needs to be done, and we need to incorporate new science so we can understand what we are doing.”

Margaret Hamburg

FDA Commissioner Margaret Hamburg delivered this year’s keynote speech in front of a packed room of pharma and bioscience personnel at the 46th annual meeting of the Drug Information Association, which opened Monday morning. Hamburg started her speech by explaining how her earliest goal as FDA chief was to build the field of regulatory science—an area hasn’t received the focus or the dollars it needs to advance.

“How do we make sure that we fully translate research into real-world products and programs that really matter?” Hamburg asked. “We all recognize that a gap has formed between bioresearch and the development of those products. With the disclosure of knowledge and capabilities emerging from many domains in research from around the globe comes the fundamental question: How do we make sure that we fully translate the potential and promise of that research into a real world product and program that really matters?”

Hamburg noted that a gap has formed between biomedical research and the development of new medical products, and urged industry to work with government to help close that gap.

She also said that industry is lacking the science and tools to assess and evaluate safety and efficacy. In other words, the US needs to beef up its regulatory science. “Billions of dollars have been invested in biomedical research, but this research will not translate into real life therapies for those that need them until we make an appropriate investment in regulator science,” Hamburg said. “We can no longer rely on techniques and approaches of the 20th century for the preventions, treatments and cures of the 21st century.”

According to the commissioner, new advancements in regulatory science can make the difference in speeding evaluation of new products, tracking safety, recognizing potential problems early on, and helping hone in on drugs that work or that have specific side effects to a targeted sub-population of patients.

Hamburg listed some opportunities for regulatory sciences.

1. Promising research is underway using stem cells for brain function loss in the case of Parkinson’s disease and treating other medical conditions.
2. NIH, industry, and foundation are working together to create an artificial pancreas for juvenile diabetes, which would continuously monitor patients’ blood sugar and automatically inject the proper amount of insulin.
3. Basic research is identifying potential tumor markers to indicate whether a patient’s cancer will respond to a specific therapy.

However, she pointed out that none of these treatments will come to fruition unless regulatory science is improved to help turn raw research into actual products.

She talked about FDA’s new initiative to work with TB researchers and companies to help create combination products, thereby fast-tracking much-needed treatments to patients in underdeveloped countries. “In might not be a sexy as discovery, but regulatory science is a dynamic and essential part of our scientific enterprise,” Hamburg said. “We want FDA to serve as a gateway, not a barrier, to the products that people need and count on every day.”

Hamburg said that the number of foreign products product US patients use has increased significantly. “The numbers are mind-boggling,” she said.

Global Security

“This year, about 80 percent of the active pharmaceutical in drugs we consume come from outside of our borders,” Hamburg noted. while acknowledging the recent mess with the tainted heparin and the growing number of counterfeit drugs. She said that oversight has to keep up with the growing global economy. This includes adding more sophisticated security strategies and establishing foreign offices.

“FDA will never have the resources to inspect every foreign manufacturer or every shipment of product from overseas,” Hamburg said. “The truth is that we need new approaches.”

She suggested building a global channel that everyone shares, and building stronger relationships with sister regulatory bodies and overseas pharma companies.

“Today, we are involved in a large amount of international activities including efforts to harmonize scientific standards, share technical expertise, and provide training in applicable regulatory disciplines and import requirements,” Hamburg said. “Public health protection is a global endeavor…that is a win-win situation for all involved”

FDA wanted to find out what people really think of the risk information printed on the back of pharmaceutical advertising. Surprise, people tend to absorb far less information from the giant blocks of text printed in drab language.

DDMAC social science analyst Amy O’Donoghue explained FDA’s recent study results to an audience of marketers at Drug Information Association’s annual meeting, yesterday.

“We recognize the current situation where pharma can just reproduce risk information written to doctors in print ads,” O’Donoghue said. So, we looked at current format and different ways of presenting the information and what format.”

The first study examined how people use the current brief information to determine if risk info and med condition affect the time people spend reading the ad, the comprehension of the info, the selection of topics, and the intention to ask a doctor.

FDA created a fake drug called Oncazil, which they used to treat asthma, high cholesterol, excess weight and produced low risk ad or high risk ads for each disease state.

Of the 800 people that saw the ad, most of the, were more worried about the heart valve damage risk in the high-risk advertisement. The average reader spent 26 seconds reading the promotion page and 41 seconds reading the brief summary.

“The conclusions we reached are that the presence of a serious risk did not change the time spent on either page,” O’Donoghue said.

In another study, FDA only looked at overweight drugs. They studied the different formats of brief summaries to see which format presents risk info in the most digestible manner.

• Traditional summary has risk info buried in a giant mix of text in three columns, on back page.
• Q&A format has less info and is more of a dialogue.
• Highlights section is more reader-friendly.
• The drug facts box version was designed similar to the OTC brief summary.

This was a mall intercept campaign and was computer administered, however the screen was the size of a magazine page. 300 people were interviewed.

FDA found no difference in reported intention to ask doctor or differences in risk/benefit tradeoff. Self-efficacy differed by format and people who saw the drug facts box were more confident that they understood the risk information than on the traditional summary.

Most people were positive about the drug facts ad box and the traditional received the lowest marks. People had a significantly more positive attitude towards the highlights and drug facts (54 percent).

“People who like a format more might spend more time on the ad and get more out of it,” O’Donoghue said. “FDA hasn’t outlawed any format, but additional studies will be done to determine content of brief summary forthcoming.”

At the Drug Information Association’s annual meeting, Pharm Exec got a few minutes to talk with a little software company named Microsoft’s about its work in creating integration between electronic data capture [EDC] and electronic health records [EHR], and its new Amalga technology.

Electronic Data Capture Integration
“I don’t think electronic data capture has evolved to where it should be yet – It’s not an adult yet,” said Microsoft life science strategist Les Jordon. “Companies say that they have a mature application, which is true, but we’ve got a lot of mature applications and everyone’s spin on EDC is slightly different. Where we see EDC going is really a merger of clinical trials management, which includes project management, electronic data capture, and integration with electronic medical records.”

Microsoft expects this merger of data sources will provide a seamless environment, so that pharma companies can find trial sites a lot easier and lower the expense of recruiting trial sites and maintaining them.

A pharma company can look at the different sites they want to use and choose one that uses technologies that can be joined with an existing EDC system. All it has to do is connect its electronic medical records with a Web service to an in-house EDC system. That significantly lowers the cost of entry for a trial site to be used.

Still Standardless
One of the biggest problems with electronic records is the lack of standards. Take one look around DIA and you see dozens of companies touting their wares, but none of them work together. So a trial site must deal with a different system for every client and vice versa.

Microsoft is working with the Clinical Data Interchange Standards Consortium (CDISC) and other facilitators to adopt a standard for integration of the EMR and EDC. “Are we there yet? No,” said Jones.

The way the integrated platform will work is that the EMR will call into the EDC system and state that it has a patient on a particular clinical trial that needs a specific form to fill out. The EDC system then will send the form over to the EMR, which then will display the form in a Web browser. The physician can then fill out the form while the patient sits in the visit. Once completed, the form is then sent back to the EDC system.

“It’s the evolution of what we call single source – a project Microsoft started with CDISC seven years ago,” Jordan said.

Microsoft is pushing an open standard that will work with any system over Web services using CDISC and SAFE standards.

“We’ve been pushing along the players and trying to get some harmonization in the IHA to get this done,” Jordan said. “For us the biggest hurdle has been the development of standards. One of the beauties of open standards is that they are open, but one of the downfalls of open standards is that they are open. That’s the problem. We have to drive consensus between parties with different interests.”

Amalga Life Sciences
Microsoft revealed new information about its Amalga data integration/aggregation engine that allows companies to point data from disparate sources into Amalga and return relationships among the data.

The key word is relationships. It’s an inference engine that looks at all the clinical trials that are going on, existing early stage discovery data bases, lists of publications – any source that the company would want to point it to – and see what the relationship is between the data.

The program visually shows all the different ways data is related. For instance, there might be a biomarker that a particular compound in a certain set of individuals would lead to a particular adverse event, Jordan said. “We can prescreen for that and tell physicians not to prescribe to patients with this particular biomarker or that it’s more effective for patients with a particular biomarker,” Jordon said.

The system was boosted by Microsoft’s recent purchase of Rosetta, a genomics analysis software, previously owned by Merck. No word yet on how that data system will be incorprated into Amalga.

A Sanofi Aventis employee complained about the 14 warning letters and asked why the practice of purchasing sponsored links on search engines, without fair balance information, was allowed to go on for so long if it was wrong and what else should companies be looking at that they might not know is wrong.

“If you do not know, of if you are not sure [if an ad is okay], submit a proposal for advisory comments,” said Kristin Davis, deputy director, DDMAC. “We have limited resources – the fact that you didn’t hear from us, just like the fact that you went 15 miles over the speed limit on your way to work – doesn’t mean that it’s okay. It just means that the cops weren’t on the road that day. Unless you have advisory comments indicating our opinion, you are not insulated from enforcement action. Especially if you are exploring some new tool and you are not exactly sure, I really encourage that you submit for advisory comments. We prefer that to sending out enforcement letters.”

Davis made it clear that the sponsored link letters were for ads where the pharma company has control of the content, so that the organic search results from Google’s search algorithms are not what FDA is looking at. FDA is targeting sponsored ads on sites like Google and Yahoo where the company has purchased a link space and created a message to be submitted on a Form 2253.

Another audience member commented that the link ads are more like the front cover of a brochure, in that the pharma company’s intent is not necessarily for that sponsored link to be the end, but to be the beginning.

“If you go to a physician’s office and you see the different brochures, you look and see which one you want to take,” she told the panel. “I looked at a lot of those sponsored links that got a letter, and when you click on them, it’s like turning a page.”

What she was referring to was the “one-click rule” that many companies felt was an unwritten rule allowing them to have risk/benefit information within one click of the sponsored link ad.

“It is the Internet, so you can’t turn a page, but you can click through,” a third person argued. “I’m just trying to figure out the guidance now, because it was 14 letters – Where do we go from here.”

Davis replied that only a fraction of the audience ever clicks through to the link page and never sees the risk/benefit information, therefore they should be considered standalone ads.

“Because you are on the Internet, you can’t forget all the regulatory requirements that apply, whether it’s labeling or advertising on a pen,” Davis said. “You’re not going to be putting your indication and think you are somehow exempt from the requirements to disclose risk information. If you can fit in some benefit statement, you can incorporate risks. If you can’t because you are limited by the amount of characters you can include, don’t only convey the positive without the negative.”

She restated that FDA’s regulations are clear on what pharma can and cannot do in terms of failing to disclose some of the required information.

The panel said that FDA is considering social media guidelines and that the topic is a priority.

In related news, the DDMAC user-fee program will not be coming back any time soon. It was not covered because it never went into effect. The voluntary program to get TV ads reviewed within 45 days lost its authority and won’t be revitalizing the program any time soon, one panel member said. Instead, Congress appropriated fundings for DTC advertising activities and created an additional review group within DDMAC.