There are innumerable questions raised by the labyrinth of billing options when CROs attempt to get Medicare coverage for a clinical trial. However, they all boil down to one: will my trial be covered?

In a live audio conference titled Medicare Coverage for Clinical Trials, (hosted by HCPro, Nov 21,) Bill Sarraille, JD and Paul Kalb, MD, Esq., tried to answer as many of the mysteries surrounding Medicare coverage as they could in an hour of presentation, and a half-hour of Q&A. They are both partners at the national law firm Sidley Austin Brown & Wood LLP, specializing in healthcare law.

Could a combination product under IND get Medicare funding? That was an area that was yet to be resolved, answered Sarraille. What if a Medicare HMO refuses to pay for an approved NIH study? That should be a billable trial, Kalb responded. Other questions poured forth: What about emergency and compassionate use of nonapproved devices? And trials sponsored by companies? And who says a test is routine? 

The confusion comes because, like a fractal, each Medicare rule has an exception, which in turn has an exception, and so on. The main rule is: no payment for clinical trial research. The main exceptions are for experimental trials both reasonable and necessary for the beneficiaries.

Sarraille then gave an example that added even more confusion. That is when the original Medicare-covered malady becomes something that needs to be, and is, treated with an experimental therapy. In this ambiguous case, the original treatments may not be covered, if they are deemed to be a precursor to the experimental therapy. Its a rule where intent of the care matters: was a set of blood tests done as a precursor to a device implantation or just for good practice?

The group designated to determine if a treatment is covered often has an evaluation to make beyond a rubber-stamped yes or no. In this case, even though Medicare is a federal institution, the decision-makers who apply the rule are at the state and local levels. This is a problem for multisite contract research organizations, since the same trial by the same CRO may get approved for coverage in North Dakota while being denied in North Carolina.

Medicare covers all routine costs for beneficiaries of approved trials, so its important to know what the government considers not routine. Any items and services provided solely to satisfy data collection and analysis arent covered, for instance. So a series of CT scans must benefit the patient as well as the statistician to be eligible. Any services used to determine if a patient is eligible for a trial arent covered, either.

Most controversial of all, no services that are customarily provided for free to the patient by the research sponsor are covered. I think this is a poor ruling by the government, Sarraille said, because whos to say whats customary? A CRO will have to be very familiar with its fields of study, specifically the billing practices, to know whats customary in the industry.

Exceptions can even be found when considering if a treatment is Medicare-covered or not. In cases where theres an approved study on a noncovered item or service, for instance, Medicare will pick up all routine costs of the trial except for the item or service in question.

CROs must first find out if they are to receive funding at all before asking how much they will get. There are two avenues to receive Medicare funding for a clinical trial. The first route is for Category B medical devices being used with FDA protocols. So an approved cardiac stent would probably be approved for use in a not-yet-indicated part of the body. 

The second exception for qualifying clinical trials is the trickier ruleone with several subexceptions. To qualify, a trial either has to be approved by a board of overseerswhich hasnt been created yet and therefore isnt an option right nowor has to be deemed qualified by already being vetted by another governmental branch. That covers trials funded by groups like the VA, NIH and CDC, as well as trials under INDs from the FDA.

That board may not be assembled for a few more years, due to pressures from Washington. The government is not committed to a timetable to create this board, Sarraille said, hinting at a political morass that makes Medicare funding resemble a traffic-free highway.

 If all this confusion isnt enough to make you anxious, theres also danger. Incorrectly filing for Medicare coverage could lead to fraud investigation not of the patient but of both the principal investigator and the billing provider. And recent federal Civil False Claims Act cases for bad billing have been settled for eight-digit figures. 

The settled false claims cases, though, were often brought by whistle-blowers who, under the qui tam provision, can receive a portion of the settlement up to 30 percent. In the three cases Kalb discussed, with settlements of $10.8 million, $2.6 million and $32 million, there appeared to be purposeful fraud instead of an understandable confusion over correct requesting and proper HIPAA notification. But no CRO wants to prove, under threat of a multimillion dollar lawsuit, that they were merely ignorant of the law instead of willfully fraudulent.

As with most government regulations, the fewer red flags your form raises, the better. Kalb and Sarraille agreed that, for instance, there could be trouble if a line in a contract stated that the sponsor will pay for costs for careif Medicare didnt pick up the tab. That would raise some eyebrows, Kalb said.  

All the oversight and paperwork are to ensure that only medically helpful research gets compensated. If youre giving an experimental treatment to beneficiaries when they would be receiving a traditional Medicare-covered treatment otherwise, your trial should probably be covered. On the other hand, if youre repeating an already-established experiment with no new differences, or running tests to benefit your client but not the patients, maybe the government shouldnt be footing the bill.

Kalb concluded with some words of wisdom. Be careful, be cautious  and go ahead and ask before you go ahead and bill. 

Articles

Latebreakers

Two experts share their wisdom on how to correcly apply for Medicare coverage for clinical trials.

Medicare Trial Coverage Sometimes a Trial Itself

Our relationship with technology is often love/hate. When it works well, it can lead us out of a morass of paperwork, into an organized, efficient digital world. Technology can be the beam of light from a lighthouse, guiding a boat safely home. The introduction of spreadsheets must have felt that way to accountants and business planners everywhere. However, technology can also be the Sirens of Homers Odysseybird-like creatures with womens heads whose song would lure sailors to their death on rocks. Lets analyze three compelling technologies to determine which, in 2004, will be the lighthouse and which the Sirens.

Before we start, let me tell you that the three technologies I am discussing are likely to be valuable, productivity-enhancing, and successfuleventually. The question is which one will be ready for prime time this year, and which will have to wait until next year, or maybe 2010? The three technologies I will discuss are instant messaging (IM), single sign-on (SSO), and handwriting recognition.

When thinking about the implementation of any new technology, we need to ask some probing questions. Does the technology solve a real business problem or one that has been created for the technology? Can it be integrated into my daily workflow? Is the technology mature? Does it require bringing together a number of different technologies/participants? Does it add work to my day? With any technology, the successful implementation requires a balance of people, process, and technology considerations.  


Instant messaging (IM) is a good place to start. This technology grew up alongside a whole series of (pre-) Internet technologies, including email, mailing lists, and bulletin board technologies. These communication technologies run along a spectrum of immediacy.  The technology that is least immediate is the bulletin board, where people can post messages in threaded conversations that may or may not be read. It is a classic pull technology, where the reader must actively seek out the information, or it is never communicated. Next in immediacy is email and the mailing list. Both involve delivery of messages, but email is a warmer medium in that it often demands a response (excluding spam and corporate memos, that is). Finally, we come to IM, a hot medium that demands a more or less immediate response.

Since it is core to our discussion, I will briefly explain IM and its impact. I preface this explanation by telling you that I was recently explaining the impact of IM on teenagers and college students to a group of CRAs/CRCs in a training course and slowly caught on, to my embarrassment, that more than 90% of them were very familiar with IMI was the one out of touch. IM involves the installation of an application on the desktop that allows you to communicate with your friends and colleagues one at a time, in groups, or in many parallel discussions. The IM application announces to your correspondents that you are on your computer and available for a conversation, and displays to you the names of people who are available. Anytime you feel the need, you can start up a typed conversation with one of these people, and they will get the message instantly. Through IM you can have a brief discussion, or a prolonged one.  

Instant messaging is becoming pervasive in home life in the United States. Older kids can sit by the computer having simultaneous IM conversations with 5 or 10 people. The first thing that new acquaintances do when they part is exchange IM screen names. Through IM, kids can keep in touch with distant relatives and old friends in real time. Parents are using IM to touch base with their kids at college in an ad hoc fashion. IM is being used by 50% of Internet-enabled households in the United States, a staggering number. IM has also begun to show up in major corporations where it is intended to enhance communications and increase productivity. 

There are several limiting factors to IM adoption in the corporate workplace. To begin with, the lack of compatibility between the various IM offerings (AOL IM, Windows/MSN Messenger, and Yahoo Messenger) is an issue for intercorporate communications. As of this writing, there seems to be a definite difference in the users of the various services, with AOL IM appealing to young adults and families, and Yahoo appealing to a somewhat more sophisticated IT audience. As with many things, Microsofts offerings in this arena are doing the best job of capturing corporate interest, in part because IT buyers expect them to increasingly integrate with other Microsoft Office products. Furthermore, most corporate IM is within a single corporation, so the merging of different IM technologies is only an issue for people who want to communicate with their families outside corporate walls.

One issue with corporate IM is the noncorporate use of the technology. In a recently published survey, up to 80% of employees admitted to gossiping while at work using the IM technology, 64% used it to complain about management, and almost one-third used it to flirt. In fact, only 27% of people said that they confined their uses of IM to business purposes. This type of behavior is problematic for companies and certainly doesnt increase productivity. One behavior identified as negative is conspiring during conference calls. In my view, this is one of the more valuable uses of IM. When members of a company want to be on the same page when speaking with a customer or partner, but they are in different locations, how better than having a back-channel conversation on IM during the conference call?

Another issue is that standard IM conversations are not recorded to be available for future review, as emails are. In fact, corporate implementations of IM now typically include the capability to capture all IM conversations. This fact, if known to employees, should reduce the occurrence of gossiping/flirting.

The potential of IM in clinical trials is related to the instant communications that it enables. Specifically, those little questions that a site might ask a medical monitor can be answered without a phone call, and without a major disruption in the workday. Similarly, project-related questions can be addressed quickly during the normal process of work. When properly installed and supported, the IM conversation stream can be fully logged and recorded, enabling it to become part of the record of clinical trial correspondence.

IM is being tied into other tools that enhance collaboration. With one menu choice in an IM application, it is possible to start a voice conversation from the microphone that is part of modern laptops, or send a file. In addition, a whiteboard can be shared between two people in an IM conversation, allowing them to share ideas and concepts. Finally, it is fairly easy to invite someone to view an application that you have open on your desktop. Any application, not just Microsoft Office, can be shared so the person with whom you are conversing can actually control it. The major limiting factor in using these capabilities in a corporate setting is educating the user that they even exist.


A second technology that is currently generating a lot of interest is single sign-on (SSO) technology. I am sure you are familiar with the problem that SSO addresses: the proliferation of passwords for all the Web sites and applications that you use. While you may get away with using the same simple password over and over again on commercial sites, most corporate applications have different requirements.

 An electronic data capture system, for example, might require an eight-character password composed of small and capital letters, numbers, and symbols that gets generated randomly. Another application might require a passphrasea series of four or five words. Each may rotate every few months, and sooner or later, we are all tempted to write them all down and post them on the corner of our monitor on a Post-It note.  Of course, the whole idea of a secret password breaks down at this point.  

Single sign-on promises to answer this particular problem. A single sign-on solution might be implemented as follows: Each morning you would open up an application or Web browser to a particular page and sign in. Perhaps you would use a username/password, or maybe a SecureID card. You might even use a smart card, containing your digital certificate.  In any case, once signed in, all your applications would become available to you. The portal application may securely store your applications passwords and make them available to each application on demand, or it may be linked into the security module of each application, allowing each to start without requiring a further password entry. 

In fact, the technology required to sign up for Windows Messenger (Microsofts version of IM) includes a type of single sign-on unique to Microsoft, known as Microsoft.Net Passport. This Passport is, in fact, an attempt by Microsoft to provide SSO over the Internet. Once logged in, you can be automatically logged into any number of Web sites that have a trust relationship with Microsoft. If you sign up for an MSN Wallet and provide your credit card information, you can automatically buy merchandise from a variety of Web sites without entering any additional information. Microsoft is hoping that others will adopt this technology and build it into their applications, creating a universal single sign-on. This type of single sign-on is a centralized model where a central server provides authentication, and then communicates with the other applications/Web sites, passing the authentication information to them. Centralized models of SSO have some issues, especially for users outside of the corporate network, who may be forced to log onto the network to get passwords for their local applications.

Another type of single sign-on is client-centric SSO. In this scenario, the passwords are stored on the local machine. This approach requires the installation of some specialized software on each computer, which contains the passwords and provides them when needed. Except in highly customized solutions, this may be a manual process, whereby a user instructs local software to apply a password to a Web site or local application. The disadvantages are those of any local applicationlocal support, validation, interactions with other programs, and the security risk of having passwords available outside of a controlled server environment. There are several shareware programs available on the Internet that can perform this function.


The third technology worth mentioning is handwriting recognition, one of the Holy Grails of computing. Ideally, a computer would be able to take handwritten text and accurately convert it to text. Handwriting recognition offers a lot of advantages to the user. First of all, the capture of information is more natural for many people. Writing can be focused on the task at hand, rather than typing errors. Furthermore, with handwritten documents it is easier to mix and match symbols, drawings, and other nontext items with text. Finally, with most modern handwriting recognition software, it is easy to capture individual key strokes as part of an audit trail and to authenticate the author based upon the style and tempo of their writing.

Handwriting recognition is best when whole words are captured, rather than individual letters. This is because errors in detection of a particular letter can be obviated by recognition of a whole series of letters together, making a word. This recognition is obviously dependent on a reference dictionary for which the match is performed. To optimize recognition, it is best to have a small dictionary and a small number of possible words. The very nature of clinical trials makes this requirement very difficult. When words are used that are not in the dictionary, there is no end to the amusement this can bring (see sidebar).

There are two different approaches that can be used separately or combined with the recognition of handwriting when handwriting is being recognized through the individual strokes of the pen. The first is asking people to adopt a particular writing style. The use of Graffiti in Palm Pilots is a good example of this technology. Unfortunately, it is difficult to get uncommitted people to change something they have been doing the same since they were in kindergarten. The next approach is to train the computer to recognize the strokes and shapes of letters that you use. This approach again requires some hours of writing to train. However, with some work it can currently give very good results.

Handwriting recognition has had a long and somewhat checkered history. The earliest commercial applications were in optical character recognition: typically the recognition of handwritten text after its completion. In fact, this technology was applied to clinical trials and is still in use today. Scanned or faxed CRFs can have some fields that are pretty easy for a computer to readare they checked or are they not checked?  However, other fields may require numbers that can be confusing (7 and 1 can be confused in Europe; 4 and 9 worldwide), or, worse, words. Words and sentences are amongst the hardest for OCR technology to recognize, and they require a fair amount of manual interpretation. The problem for optical character recognition (OCR) and all other handwriting technologies in a clinical setting ishow large an error rate can we accept for the capture of primary data0.1%? 1%? 10%? The lower numbers are very difficult if not impossible to achieve. More to the point, identifying and correcting the errors is inefficient, time-consuming, and error-prone.

Handwriting recognition in real time has been around for several decades, but the technology entered the mainstream with the introduction of the Apple Newton, the predecessor of todays personal digital assistants (PDAs) that included a technology to learn native handwriting based on dictionary matches. Many swore by the device, while others swore at it. The fanfare associated with its introduction was deflated within the first week, when Garry Trudeau published a Doonesbury comic that lampooned the technology and its users. He had a character enter Catching on? and the Newton translated it as Egg Freckles. Some say that the strip was almost single-handedly responsible for sinking the technology. In fact, Apple continues to work with the underlying technology, incorporating it in their operating system.

Later attempts include the IBM/Cross Pad, which recorded pen strokes, and the Palm Pilot and similar technologies, which are dependent on modifying the users handwriting style. Microsoft has incorporated handwriting technology in its latest Tablet PC operating system, and its accuracy has predictably been the subject of some criticism. 

The most recent entry into this field is the Anoto Pena quite different version of digital handwriting capture. Briefly, the pen contains a minute camera that captures the configuration of tiny, almost invisible dots on special paper. The dots are cleverly arranged so that the pen can identify and transmit the exact location on any piece of paper of a pen stroke. The pen captures individual pen strokes and can transmit them to a local or central computerproviding the equivalent of a photograph of the page with an audit trail for each pen stroke. In the end, though, the technology is dependent upon, and subject to, all of the foibles of the current state of the art of handwriting recognition.

Unfortunately, handwriting recognition has failed to reach a sufficient level for regular, reliable data recording. While recognition algorithms are improving, they still require manual review and frequent correction to achieve 100% capture. This is almost the same problem with OCR. While it is often possible to develop a confidence interval for recognition, this will only identify the low likelihood matches. In order to catch all errors, it would almost be necessary to look at every word. This would eliminate the advantages of handwriting recognition.

So, we have three technologies. Which fulfill the original criteria? Which give proper balance to people, process, and technology considerations. As mentioned, they all solve important problems, and they all can integrate well into a work environment. It is in maturity of the technology that they vary. IM technology is becoming mature and will only improve over time. SSO technology is still young, and many different versions are available. It is not yet clear which will prevail, or if this is even relevant. SSO may be the kind of technology that each company implements independently. Handwriting recognition is great for PDAs and other noncritical uses, but will be challenging if used in regulated data collection, such as clinical trial data management. 

Handwriting is a people-  and process-oriented technology, but fails on technology availability for mission critical applications. SSO works from a technology and process perspective, but will take significant re-education efforts when implemented. IM, though, has an established technology, a clear process, and is very strong on the people side; nontechnical people often enjoy using it. Of the three technologies discussed, IM is closest to being our lighthouse, while handwriting recognition currently threatens to dash us into the rocks.

SIDEBAR: Lewis Carrolls Jabberwocky, as recognized by the Apple Newton


(You can find the original Jabberwocky in Through the Looking-Glass and What Alice Found There, 1872 or at http://www.jabberwocky.com/carroll/jabber/jabberwocky.html)


Teas Willis, and the sticky tours
Did gym and Gibbs in the wake. 
All mimes were the borrowers, 
And the moderate Belgrade. 
Beware the tablespoon my son, 
The teeth that bite, the Claus that catch. 
Beware the Subjects bird, and shred
The serious Bandwidth! 
He took his Verbal sword in hand: 
Long time the monitors fog he sought, 
So rested he by the Tumbled tree, 
And stood a while in thought. 
And as in selfish thought he stood, 
The tablespoon, with eyes of Flame, 
Came stifling through the trigger wood, 
And troubled as it came! 
One, two! One, two! And through and though, 
The Verbal blade went thicker shade. 
He left it dead, and with its head, 
He went gambling back. 
And host Thai slash the tablespoon? 
Come to my arms my bearish boy. 
Oh various day! Cartoon! Cathay! 
He charted in his joy. 
Teas Willis, and the sticky tours
Did gym and Gibbs in the wake. 
All mimes were the borrowers, 
And the moderate Belgrade. 


It seems very pretty, Alice said when she had finished it, but its rather hard to understand! (You see she didnt like to confess even to herself, that she couldnt make it out at all.)
 Lewis Carroll, 

Technology Viewpoint

One new idea that?s ready for use; another that will be soon; and a third that?s not yet there.

Three New Technologies for 2004

They made it! Despite everything you may have read about the European Union being unable to agree on anythingfrom a new constitution to how to keep budgetary deficits in checkthe 15 current EU member states managed to agree just before the year-end on its new regulatory framework for pharmaceuticals. After more than two years debate, consensus was reached in late December on the major points of divergence among the key players. The result is that the new rules will come into effect about the same time that the 15-member EU enlarges to become a 25-member EU, with 10 new countries from the former Soviet bloc and the Mediterranean.

The new rules are extensive in their scope, so they will have many indirect effects on the clinical trials community. They also contain some specific changes that relate directly to clinical trials.


First, the big picture. The likely principal consequence will be a more efficient authorization system for innovative medicines. The role of scientific advice in the authorization process will be strengthened, and in the European Agency for the Evaluation of Medicinal Products (EMEA), increased flexibility will come from the creation of different specialized groups and the possibility of using experts from outside the EU.

Erkki Liikanen, the European Commissioner responsible for the pharmaceutical industry, greeted the vote as an important day for European patients and the European pharmaceutical industry. He said it will ensure a high level of protection for public health, while improving access to medicines and boosting the competitiveness of the European pharmaceutical industry. 

The basic principles of the existing system are retained, with the co-existence of two regulatory procedures, one centralized and one decentralized, based on mutual recognition. The changes will open the centralized procedure to new types of medicines: it will become mandatory for medicines to treat AIDS, cancer, diabetes, neurodegenerative disorders, and orphan diseases, and after four years this will be further extended to cover medicines for autoimmune and viral diseases. A general review clause could also allow for further extension to other conditions.

The new rules will also introduce a new fast-track authorization procedure for products of significant therapeutic interest. In addition, there is the possibility of a conditional one-year authorization where there is an important expected health benefit for the patients concerned, and a pan-EU compassionate use provision for products before authorization. 

The fast-track registration procedure for these products of significant therapeutic interest is a mirror of the similar accelerated process in the United States. It will reduce review time by at least two months30 days faster than the U.S. system for priority review, claimed Liikanen. 

The conditional marketing authorization will allow for a one-year authorization to be granted, provided that there is an important expected health benefit for the patients concerned, and provided the company agrees to carry out additional monitoring and clinical studies, which will be reviewed at the end of the year. The new provisions for compassionate use will allow the supply of medicines for compassionate reasons to a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorized medicinal product. The medicinal product concerned must either be the subject of an application for a marketing authorization...or must be undergoing clinical trials. 

According to Commissioner Liikanen, this will help to ensure that patients are not discriminated against on the basis, in particular, of the location of the clinical trials performed by a particular company. He said it will allow patients successfully treated in a clinical trial to continue treatment during authorization assessment.The changes should also improve the transparency of procedures and decision-making. More access will be provided to the results of the EUs decision-making process on pharmaceuticals. 

And there will be some tighter monitoring of medicines on the market, in response to widespread criticisms of failings in the European system. Just before the final vote on the package of proposals, the influential European consumers association, BEUC, issued a statement claiming: Throughout Europe, only around 1025% of adverse reactions experienced by patients are reported to the relevant authorities. The system of reporting by health professionals is not working as it should. It is essential to allow patients to report directly about the side effects they experienced.

During the first five market years of a new medicine, side effects must be closely monitored, it went on. Often we do not know enough about the safety of a medicine until it has been exposed on a longer term to a much wider range of people than is possible through clinical trials. The surveillance of side effects will become even more important with new fast track procedures.

European citizens are being unnecessarily exposed to medicines that may not always be safe for them, said Jim Murray, BEUC Director, adding: It is in everybodys interest that medicines are closely monitored. The actual experience of patients is the first and essential step to a more effective monitoring system that facilitates swift action where necessary and better information sharing. Direct reporting of side effects would allow patients and doctors to make better choices. 

Additional protection will be provided to data generated in support of marketing authorization applications. Protection of data submitted by companies for the approval of medicines will be harmonized so that it will not be possible to market generic copies of a product anywhere in the EU until 10 years have elapsed from its first EU authorization. This can be extended by an additional year if a further innovative indication for the medicine is authorized. One year of data exclusivity will also be granted on the studies that allowed the switch of medicinal products from prescription only to nonprescription status.

But there will be more vigorous competition from copy products, since the new rules will allow the generic pharmaceutical industry to start testing their products in Europe two years before the end of the data exclusivity period for the reference product.There will also be clearer rules for copyingwith new definitions of generic medicines and of biosimilars, as copies of biological products have been termed. Even the U.S.-based Biotechnology Industry Organization took the unprecedented step of issuing a comment on this aspect of the agreement. 

President Carl B. Feldbaum said of the new rules requiring tests for biosimilars: The EU recognizes that biosimilars are different from existing biological therapies in terms of their raw materials and manufacturing processes and that even slight differences can significantly alter a biological therapys safety and effectiveness. Therefore, the EU will require companies that produce biosimilars to conduct appropriate tests. BIO supports the EU in its decision to require extensive tests for biosimilar medicines. Biological therapies are vastly different and more complex than conventional chemical drugs. As the EU correctly concluded, even slight changes in the therapies themselves or the processes used to create them can create significant differences in their safety and effectiveness. Without adequate clinical tests, patients cannot be assured that their biological therapies are safe and effective.


Greater focus on the quality of testing and trials will direct more attention to the conduct of clinical trials. The starting point for this initiative is agreement on the need to provide for the ethical requirements of the EU Clinical Trials Directive1 to apply to all medicines authorized in the EU.

So, the European Commission and the EMEA will be given additional responsibilities for checking on how industry and trial centers behave. They are to be given the task of coordinating the execution of the various supervisory responsibilities vested in the Member States, and in particular with the tasks of providing information on medicinal products and of checking the observance of good manufacturing, laboratory, and clinical practices.

The new rules will also lead to increased attention to the conduct of clinical trials outside the EU. 

In particular, the new rules say, 
with respect to clinical trials conducted outside the EU on medicinal products destined to be authorised within the EU, at the time of the evaluation of the application for authorisation, it should be verified that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of the directive.


After vigorous debates in Europe over two years, which had increasingly focused on the question of intellectual property protection in a battle between the research-based and generic sectors of the pharmaceutical industry, the EU members agreement was met with an outbreak of unaccustomed consensus among most of the European lobby groups.

The principal associations representing the European biotechnology and innovative pharmaceutical industry were critical of concessions made to the copy industry, saying the signal given to research was not encouraging. But the criticism was mutedand Commissioner Liikanen said he was happy at their moderate reactions.

European producers of generic medicines endorsed the new rules. The European Generic Medicines Association said whilst there could be delays in patient access to affordable healthcare caused by increased periods of data exclusivity, the law will nonetheless create the foundation for a more efficient regulatory system for the authorisation of all medicines in the European Union.

It was among patient organizations and health insurance corporations that the most criticism emerged: they spoke of a sell-out to big pharmatheir term for the lobby of the international pharmaceutical industry. The European Medicines Forum, a coalition of health activists and patient groups, lamented what it claimed was the inadequacy of compassionate use provisions, the failure to give patients a bigger role in pharmacovigilance, and the huge costs that would result from allowing more intellectual property protection to big pharma. They were particularly hostile to the outrageous prolongation of clinical data protection.


Meanwhile, at the same time the EU was agreeing its new pharmaceutical rules, an influential health-sector think tank in one of the most influential EU member states was expressing radically alternative views on the future of pharmaceutical research.

The UK Kings Fund put out a provocative report2 which claimed that research in the United Kingdomone of the European beacons of hope for the pharmaceutical industry-was badly focused and did not serve the interests of citizens. The current agreement between the U.K. government and the U.K.  pharmaceutical industry is focused on the wrong areas, says the report: by concentrating on researching new medicines, it neglects some other research areas that may be potentially beneficial for promoting peoples health, such as alternative therapies. Research designed to protect and promote health currently attracts far fewer resources than research focused on the search for new pharmaceuticals.

In addition, the arrangement does not fully take the needs of some major groups, including children and older people, into account. The strategic objective should be shifted towards achieving better health for the U.K. population, the report says. A reshaping of the framework...is needed if users of the health care system are to get a better deal. It needs to be widened to include citizens and service users more effectively in decision-making, and to undertake research into areas of potential health benefit other than new forms of drugs treatment.

Among the Kings Funds proposed remedies: the roles of the private sector, public sector, the scientific and clinical professions and health service users need to be reworked; the benefits of expanding the public role needs examining in the areas of basic research, precompetitive research, neglected therapeutic areas, care delivery, and clinical research and trials in areas that attract no commercial funding; and the regulatory role should be modified to ensure openness, absence of bias, high scientific standards, and the promotion of trials that promise the greatest health gains.

It is a curious coincidence that just as the EU is agreeing on a new regulatory framework to promote a research-based pharmaceutical industry, influential figures in one of the most research-oriented EU member states should be arguing so forcefully for a diametrically opposed approach.


	1. Directive 2001/20/EC of 4 April 2001 of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
2. Getting the right medicines?, Kings Fund, London, 2003.


View from Brussels

Find out what the new EU framework entails; a think tank finds that too much health care energy is going into medicine.

EU Surprises Itself by Agreeing to Pharma Rules

Federal health officials are aiming to improve patient care by establishing national electronic medical records and health information systems, which will allow health care professionals to share patient medical information more readily. The Food and Drug Administration has launched an ambitious program to support these efforts, beginning with a policy requiring drug manufacturers to submit product labeling information electronically. 

The agency is also encouraging electronic filing of investigational new drug applications (INDs) for cancer therapies and is supporting initiatives to build databases of information on product safety, efficacy, and quality. These initiatives will provide the public with timely information on appropriate medication use through national information systems based in the National Library of Medicine.

FDA has issued a number of policies in recent years to encourage manufacturers to submit regulatory documents in electronic format. In January 1999, the agency issued a guidance on formatting electronic regulatory submissions, which it updated in October 2003. FDA also published recommendations for electronic filing of the common technical document (CTD) last August. This establishes a common format for submitting clinical, preclinical, and manufacturing information to register new drugs around the world, as recommended by the International Conference on Harmonization. Other ICH standards are changing FDA policies for electronic submission of postmarketing expedited safety reports, and for periodic adverse drug experience reports. 


Until now, FDA e-submission programs have been voluntary. The agency has worked to establish uniform standards and terminologies for submitting electronic data. This will enable information systems to capture complex information on medical products, practices, and health conditions, and transfer the data over secure networks. FDA also recently clarified its electronic records and signatures policy under 21 CFR Part 11, which should encourage sponsors to develop electronic submission systems.

This progress in laying a foundation for electronic data submission and evaluation is prompting FDA to now mandate electronic data filings, starting with drug labeling information. FDA issued a final regulation in December requiring sponsors to submit the content of the package insert or professional labeling in electronic format, including all text, tables and figures.

 The rule establishes a standard format for filing labeling information for review of market applications, in supplements for new drugs and biologics, and for including them in annual reports. 

The aim is to improve the review process and speed up dissemination of labeling changes and important product information to doctors and patients. The data will become part of an electronic library of labeling information for all FDA-regulated products created by National Library of Medicines DailyMed project, which health professionals and the public will be able to search for information on drug side effects and benefits. FDA officials anticipate that this policy will greatly facilitate its review of thousands of labeling changes submitted each year. When a manufacturer files even a minor change in professional labeling, the agency currently has to conduct a manual word-for-word comparison using two paper copies.

In announcing the e-labeling requirement at the 9 December 2003 meeting of the National Council on Patient Information & Education (NCPIE), FDA commissioner Mark McClellan observed that using modern information technology to improve public health is no longer optional at FDA. McClellan expects the new program will allow sponsors to provide timely updates on drug risks and benefits, and that the information will permit physicians and consumers to make head-to-head comparisons between drugs so that they can make the best choices.

As far as new mandates go, this one is not highly controversial. Most large pharmaceutical companies have been submitting labeling information electronically for some time, and the technical process for doing so is relatively straightforward. FDA will accept electronic files in PDF (portable document format), which is inexpensive and commonly available. The agency reserves the right to recommend new file formats and software in the future in response to technological advances, but promises to consult with industry and to provide ample warning before making any changes. 

FDA published a proposed rule on this topic in May 2002, received only a few comments, and issued the final regulation with no changes. The requirement becomes effective in June and applies only to the content of the package insert, and not to all types of labeling on containers or submitted with advertising material. Still in the works is a new regulation that aims to restructure the content of professional drug labeling in order to make it more readable and useful to prescribers. 

A related initiative aims to replace paper package inserts with electronic information. Pharmaceutical companies back this program and have been working to reduce opposition from pharmacists. Tests of a paperless labeling system are underway. These policies aim to update the system for providing prescribing information to health care professionals; the goal is labeling that is clear and timely, which presents needed information on drug benefits and side effects in an efficient manner.

The e-labeling rule was issued just as FDA announced its collaboration with the National Cancer Institute (NCI) to establish the Cancer Biomedical Informatics Grid featuring an electronic system for the submission and evaluation of clinical trial information for cancer research. A first step is to implement a system for submitting INDs for cancer therapies electronically to FDA. 

The aim is to build a system that will link U.S. cancer researchers to FDA to allow electronic submission of clinical data. The process will allow FDA to review these applications faster, which will make new treatments available to patients more quickly and at a lower cost.

This NCI collaboration is one part of a broader FDA strategy for developing a national electronic health information system. At a speech before the Urban Institute in Washington D.C. in November, McClellan described his vision for using modern information technologies to collect and analyze information on medical products to deliver safer, higher value and less costly medical care.

McClellan highlighted the NCI collaboration and added that FDA hopes to use this experience with cancer therapies as a model for how we manage information across all of the different therapeutic areas and in every clinical trial. 

Working in the cancer area will further this effort because many cancer doctors and NCI cancer cooperative groups already have established advanced information systems. Investigators in these particular groups enter clinical information electronically, offering an example of how the system can speed up the clinical trial process and provide information more readily to drug developers and FDA reviewers. In addition to enhancing FDAs review process, electronic information from clinical trials will accelerate clinical research by allowing researchers to quickly obtain answers to questions about test treatments. Policy makers also expect these systems to provide useful information on drug benefits and risks for patient subgroups, including racial and ethnic minorities, women, children, seniors, and others. 

A related FDA proposal for streamlining clinical research encourages researchers to share information with FDA on how genetic differences may cause patients to respond differently to therapies. FDA officials are aware that drug manufacturers are collecting a good deal of pharmacogenomic (PG) data, but are reluctant to submit it to the agency for fear it might raise red flags for the regulators. 

 clarifies when sponsors should submit such data as part of the review process for new drugs or biologics. FDA also defines a separate pathway for providing research information apart from official submissions, to better inform regulators and the research community of new discoveries. 

The initiative involves using electronic information systems to analyze vast amounts of data that then can be made available to the medical community. FDA says it will combine PG information submitted electronically to camouflage the sponsor while generating useful information on when treatments are likely to be more effective or more safe for certain patients. 

A related FDA initiative seeks to obtain more postmarket information on new drug use. Agency officials are expanding the current spontaneous adverse event reporting system and adopting innovative statistical methods to identify signals of drug safety problems more quickly. But because the voluntary reporting system is fairly limited, FDA also aims to establish broader active surveillance systems. These will be able to scan electronic medical records for signals that could indicate problems with new drugs. Eventually, hospitals and physicians will establish electronic medical records systems, and adverse event reporting will become automatic.


The ultimate goal is to reduce prescribing errors and improve treatment decisions through electronic prescribing systems that utilize low-cost Web technologies and palm-sized information devices increasingly being used by physicians. While electronic systems account for less than 10% of prescribing today, McClellan estimates that broader use of such systems across the United States could eliminate more than two million adverse drug events each year. FDAs e-labeling policy will encourage e-prescribing, says McClellan, along with a less-noticed provision in the Medicare reform bill that supports development of e-prescribing programs. 

The legislation stops short of mandating that health plans and providers adopt such systems, but provides strong incentives for them to do so. First, it instructs HHS to establish e-prescribing standards in two years. Then, HHS will conduct a one-year pilot in 2006 to test the system and issue final standards in 2008. 

The bill also provides grants to assist prescribers in installing e-prescribing programs and, even more innovative, allows Medicare managed care plans and pharmacy plan operators to pay bonuses to doctors and hospitals that participate in e-prescribing programs. 

One year after adoption of final standards, all Medicare providers will have to follow the new standards if they want to use electronic prescribing systems. The scenario expects e-prescribing will drive formulary compliance, which should improve patient safety, quality of care, and yield cost savings.

1. Published in Federal Register, vol. 68, No. 238, Dec. 11, 2003, 69009-69020.
2. Remarks presented Nov. 12, 2003 available at www.fda.gov/oc/speeches/2003/urbaninstitute112.html.
3. Guidance for Industry, Pharmacogenomic Data Submissions, November 2003.

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