
Having realized that your prestigious magazine arrives to its 10th Anniversary this month, I am more than pleased to convey my warmest congratulations and admiration to the great and useful effort you do every month to produce so useful a guide and reference.

Country Manager, YM Biosciences
Havana, Cuba



The excellent article entitled Pediatric Drug Development by P. Kleist (

, January 2002) prompted me to make a small contribution myself.Although the experience of the pharmaceutical industry regarding clinical trials in the pediatric population is generally quite scarce, it is actually for this reason that the necessity of clinical trials in children cannot be overemphasized. The grounds lie basically in the first lesson in pediatrics taught during medical studies, which states that a child is not a man in miniature but has specificities of its own.

This means that the pharmacokinetic and pharmacodynamic properties of a drug are by no means equivalent when used in pediatric and adult populations (nor are they identical in any two individuals).

Furthermore, the ethical aspects of drug administration support the attitude that it is certainly more ethical to use a drug that was clinically studied in as many subjects as possible as a part of the approval procedure than to use one that was not. Parents of children receiving an approved drug that was previously clinically investigated in a relatively small study specimen are not aware that their children are more like guinea pigs than the children who actually take part in clinical trials (provided these are conducted in accordance with good clinical practice requirements).

Concerning the study design or, more specifically, the role of placebo in such trials, it is my opinion that placebo has no place in such trials. I believe that the latest amended version of the Declaration of Helsinki, which states that a new therapy should be compared to the best treatment available, should be strictly adhered to. In cases when this is not feasible, even a noncomparative trial is better in my opinion than a placebo-controlled comparative trial.

I believe that such an approach would contribute to a greater willingness of parents to consent to their childrens participation in clinical trials. After all, didnt most of us take part in a clinical trial during childhood unawares? (My experience with use of tetracycline syrup fortunately did not have such a drastic outcome.) Wouldnt it be better, since we are already part of this great experiment called life, that such participation be under controlled conditions?

The following idea might appear too stern, but based on the above facts as well as the literature data, I suggest that the competent European authorities in this field should follow the U.S. initiative reflected in the FDA Modernization Act, the Final Pediatric Rule, the Childrens Health Act of 2000, and the Best Pharmaceuticals for Childrens Act. They should even go a step further and consider the feasibility of making clinical trials in children mandatory, even for drugs already used for years in the adult population, that is, drugs that are well known to the regulatory authorities and the public. Therefore, the pediatric drugs would have to be clinically investigated both in the country of the manufacturer and in the country where they are to be approved.

Finally, clinical trials are never to excess. Neither are ethics nor health.

Clinical Pharmacologist
Regulatory Affairs Department, Galenika a.d.
Belgrade, Yugoslavia


Why are we going backward on the subject of privacy of medical records? Changes to the HIPAA privacy rule proposed in March by the Department of Health and Human Services (HHS) loosen restrictions on providing care before obtaining consent and discussing patient care out loud with other clinicians.

Just as the MD credential obligates physicians to adhere to the tenets of the Hippocratic Oath, the credential of RHIA obligates Registered Health Information Administrators to tenaciously protect the confidentiality of private medical information on behalf of patients at all times. Because there was never federal regulation to protect this private health information, this has been a challenging task at best. Also, patients have not always been aware of how their medical information is being used and what they can do to direct that use.

Fortunately, the Department of Health and Human Services, along with the Office of Civil Rights, has been strategically positioned by the HIPAA Privacy standards to improve this legacy while expediting patient care and payment to providers for that care. That is, it was until March 2002. 

The United States has invested between $10 billion and $15 billion dollars in health care information technology since 1996. Health care professionals have made the collection of patient data, the conversion of that data into useful information, and access to that information infinitely simpler than at any time in the past. Our government had the foresight to know that with this massive investment, we needed a system to protect this easily accessible information in the spirit of ensuring the zone of privacy it seeks to provide its citizens through various laws regarding private information.

We should proceed cautiously in modifying the HIPAA privacy regulations. Recall the original intent of these privacy regulations with these examples from the Federal Register of 28 December 2000:

	35% of Fortune 500 companies look at an applicants medical records prior to making hiring decisions.

	A health system posted records of thousands of patients on the Internet.

	A health department employee took a disk with the names of 4,000 people who had tested positive for HIV.

	A woman purchased a computer that still contained prescription records of pharmacy customers.

	A banker who also sat on a county health board gained access to patients cancer records and called in their mortgages.

Do we really need more evidence than this that we should not allow the other protectionsfor example, civil monetary penalties or imprisonment for using or selling protected health information for personal advantage, personal gain, or malicious harmprovided in the HIPAA privacy regulations to be carved away until we find ourselves back at square one?

Administrative simplification was the original intent of the HIPAA regulations. Those of us responsible for running and operating health care organizations have questioned this as we have learned more about the arduousness of implementing various HIPAA provisions. It isnt going to be easy. As leaders, its time for us to step up and figure out how best to implement these regulations, share the successful methods for doing so with our colleagues in the health care community, and maintain the protections that we as citizens have been provided.

Corporate Compliance Officer
Vice President, Professional Services
Precyse Solutions
King of Prussia, PA


Articles

Letters to the Editor

Readers respond to articles and editorials.

Just two years after the new European Union legislation on orphan drugs came into effect, the 100th recommendation of designation of an orphan drug has emerged from the EU scientific body responsible for this new branch of medicines promotion in Europe. The three latest applications to win this statusat the late March meeting of the EUs committee for orphan medicinal productsare treatments for emphysema secondary to congenital alpha-1 antitrypsin deficiency, glioma, and esophageal cancer. The scientific recommendations are also largely going on to receive formal designations of orphan product status from the European Commissionwhich is empowered under the EU procedure to give the final yes or no.

As of the end of March, 169 applications had been submitted, and 101 positive scientific recommendations had been made by the committee. Of these, 98 had already been formally approved by the Commission. The committee has reached only five negative opinions on applications. Of these, two applications were withdrawn, and three were appealed (one appeal resulted in a definitive negative opinion, one in a definitive positive opinion, and the third is still in the appeal process). Altogether, 43 of the applications submitted have been withdrawn over the two years. But the mechanism is still highly attractivethe committee has already received notifications of intent to file applications for another 47 treatments. The mechanism seems, therefore, to be earning its place.

Alongside the operation of the procedure, continuous refinements are being brought to it to improve its functioning. Further information, in the form of summarized committee opinions, is now routinely published on treatments after the formal Commission decision to designate them as orphans. The committee recently revised its guideline on the format and content of applications for designation as orphan products. And it adopted new guidance in the form of points to consider on the calculation and reporting of the prevalence of a condition for orphan designation.


The revised guideline (available at www.emea.eu.int/pdfs/human/comp/ 628300en.pdf) clarifies some of the basic requirements for a successful application, supplementing the terms set out in the EU regulation of January 2000. It provides advice on how to compile the documents that sponsors should provide in an application for orphan medicinal product designation. When regulators have gained experience with the procedure, the guideline will be updated to include more detailed explanations and examples. It also provides advice to sponsors that wish to transfer the designation of an orphan medicinal product and/or to change the name or address of a sponsorin essence, to transfer the orphan designation to another sponsorwhich requires detailed documentation of the original designation and of the intended recipient.

It adds some new definitions. For example, 

 is defined as any deviation(s) from the normal structure or function of the body, as manifested by a characteristic set of signs and symptoms (typically a recognized distinct disease or a syndrome). The guideline explains that the word 

 is used in the regulation to ensure that the regulation applies also to treatments for conditions which are not classical diseases, in particular genetic disorders. It defines 

 as the condition as defined above that meets the criteria defined in the regulation. An 

 is the proposed indication for the purpose of orphan designation. This specifies if the medicinal product which is the subject of the designation application is intended for diagnosis, prevention or treatment of the orphan condition. And it defines 

 as the proposed indication for the marketing authorization, based on the sponsors expectations at the time of the designation application. The granted therapeutic indication at the time of marketing authorization will be the result of the assessment of the quality, safety and efficacy data submitted with the marketing application and may be different to the one proposed at the time of designation application.

The guideline makes clear that an application for designation as an orphan medicinal product must be made before any application for marketing authorization is made for that indication: a previous application in any EU member state (whether successful or not) renders a product ineligible for orphan designation for that indication. To apply for more than one indication for the same product, separate applications should be submitted for each orphan indication. In this regard, treatment and prevention of the same condition are considered as two separate indications and should be the subject of two separate applications for orphan designation.

The active substance should be declared by its recommended international nonproprietary name (INN; also called generic name), accompanied by its salt or hydrate form if relevant (and if the recommended INN is not available the proposed INN should be provided). The sponsor should submit details of the proposed orphan indication for which designation is being sought (and this may be broader than the proposed therapeutic indication).

A contract research organization can be the sponsor of an orphan medicinal product as long as it is established in the EU. In all cases, names and addresses of manufacturers and sites of manufacture of the active substances and of the medicinal product (if available) should be provided. 


Details of the condition that the medicinal product is intended to diagnose, prevent, or treat should be provided, including a clear description of the disease or condition in question and its causes and symptoms. The sponsor should submit details of the proposed orphan indication for which designation is applied. This should define the target condition or disease distinguishing between treatment, primary prevention, secondary prevention, and diagnostic indications. The orphan indication may comprise a broader population than the population defined by the proposed therapeutic indication, and should be the population on which the prevalence is estimated. The indication applied for may be modified during the designation process.

A section covering medical plausibility should be completed for all applications, with details of the rationale for the use of the medicinal product in the proposed orphan indication. And where applications refer to a subset of a particular condition, a justification of the medical plausibility for restricting use should be submitted, along with methods or criteria used to delineate this population subset.

The characteristics defining a distinct condition should determine a group of patients in whom development of a medicinal product is plausible, based on the pathogenesis of the condition and pharmacodynamic evidence and assumptions. Recognized distinct medical entities would generally be considered as valid conditions. Such entities would generally be defined in terms of their specific characteristicsfor example, pathophysiological, histopathological, and clinical characteristics. Degrees of severity or stages of a disease would generally not be considered distinct conditions. The fact that a subset of patients exists in whom the medicinal product is expected to show a favorable benefit/risk profile (as defined in the proposed therapeutic indication) would generally be insufficient to define a distinct condition.

Sponsors will have to present convincing arguments to justify the medical plausibility of any proposed subset and the rationale for excluding the larger population. A subset of a disease which, when considered as a whole, has a prevalence greater than 5 in 10,000, could be considered a valid condition if patients in that subset present distinct and unique evaluable characteristics with a plausible link to the condition, and if these characteristics are essential for the medicinal product to carry out its action. In particular, the pathophysiological characteristics associated with this subset should be closely linked to the pharmacological action of the medicinal product in such a way that the absence of these characteristics will render the product ineffective in the rest of the population.

Patients may be affected by more than one condition. Generally the intersection of two (or more) concomitant conditions would not be considered as a valid condition. It could be acceptable, however, if an intersection resulted in a certain new evaluable characteristic essential for the pharmacological effect and the medical outcome. Exceptionally, the need for a particular treatment modality (regardless of underlying diseases) can be considered as a valid criterion to define a distinct condition.A statement justifying the life-threatening or chronically debilitating nature of the condition, or the seriously debilitating or serious and chronic nature of the condition, should be provided, supported by scientific or medical references.


Information on the prevalence of the condition or disease in the EU should be supported by documentation that includes a comprehensive review of authoritative references to demonstrate that the disease or condition for which the medicinal product would be administered affects no more than 5 in 10,000 persons in the EU. The guideline calls for a clear explanation of how estimated prevalence was calculated, indicating the methods and results for identifying source data and documentation and calculating the prevalence. Studies should be summarized in tabular form and include all relevant information such as definition and size of study population, case definition. 

If no up-to-date references are available, the sponsor should provide a clear basis for the assumption that the disease or condition will meet the orphan criteria. They should describe the methods and results for identifying databases of rare diseases. Information from relevant databases in the EU should be provided, if available. Where an existing database refers to the prevalence of the disease or condition in one member state, an explanation as to why it is plausible to extrapolate this data to other member states should be provided, taking into account possible ethnic and/or cultural differences. In the absence of EU databases, reference may be made to third-country databases, provided the extrapolation to the EU population is made.

Where a disease or condition has been considered within the framework of other EU actions on rare diseases (such as financially supported to improve information on rare diseases, or in the context of EU research projects), this information should be provided.

Where applications are based on the argument that without incentives, it is unlikely that the marketing of the medicinal product in the EU would generate sufficient return to justify the necessary investment, sufficient documentation should be provided, including data on all costs incurred or expected to be incurred in the course of development and marketingincluding preclinical and clinical studies, formulation studies, stability studies, literature searches, meetings with regulatory authorities, costs of supplying the medicinal product, and preparation of the application for designation. 

The documentation must indicate the number of studies or investigations performed in each case, with details of duration and timing, the number of patients or animals, and the amount of staff time involved. It should also include details on any grants, tax incentives, or other cost recovery provisions received either within the EU or in other countries. An estimate and justification is also required for the expected revenues from sales of the medicinal product in the EU during the first 10 years after authorization.

Justification is needed as to why the existing methods of treatment are not considered satisfactory or for the assumption that the new medicinal product seeking designation will be of significant benefit to those affected by the condition. This may be based on clinical information, scientific literature, or the results of comparative studies, whether of a definitive or preliminary nature.


The new documentation on points to consider on the calculation and reporting of the prevalence of a condition for orphan designation sets out in more detail the justifications required from the applicant. No matter how rare a condition actually is, it is not sufficient to state that it is obviously rare and the prevalence is far below the 5 in 10,000 limit, says the committee, which also states, Where all available data show conclusively that the population prevalence lies well-below the threshold, the fulfillment of the prevalence criterion will be a relatively simple task. In less clear situations, careful weighing of the evidence from available sources and formal numerical combinations of available data may be necessary to establish that the population prevalence lies below the threshold. 

But it goes on to recognize that in some very rare diseases or conditions obtaining relevant morbidity data to demonstrate that the prevalence meets the orphan criterion may be the most difficult task.

It is no mean feat that so many successful applications have been made already through the new system, even in the absence of this more detailed guidance. The hope must be, now that more of the administrative preparation is clearer, that even more orphans will at last find a parent to care for them.            

View from Brussels

A new guideline details basic requirements for submitting a successful application for a proposed orphan drug in the European Union.

Parents for Orphans

Clinical studies of new drugs and medical products have been growing exponentially, spurred by a steady surge in federal funding of biomedical research, and by increased investment in R&D by pharmaceutical and biotech companies. A major expansion in NIH grants has focused the attention of federal investigators and oversight agencies on the clinical research enterprise and how well it protects human participants in clinical trials. 

The Office of the Inspector General in the Department of Health and Human Services continues to examine the adequacy of protections for study participants, while regulatory agencies are expanding programs and policies to ensure compliance with the rules. Sponsors of studies regulated by the FDA face added rules governing clinical trial conduct, as well as new threats of litigation from government and private attorneys. 

Law enforcement officials are concerned that the increase in the number of clinical trials is prompting sponsors and CROs to sign up a broader spectrum of physicians, clinics, and hospitals as clinical investigators, many with little experience in research rules and practices. They question whether this growing pool of researchers is adhering to requirements for recruiting trial participants, ensuring informed consent, documenting clinical responses, and filing information on adverse events. Hospitals and physicians are eager to expand research activity to boost incomes squeezed by the tighter reimbursement policies of HMOs and government health care programs. However, they now find themselves in a whole new world of regulation and compliance requirements.

Both government officials and private attorneys maintain that the goal of heightened enforcement and regulation is to ensure that study participants are safe and fully informed of the risks of participating in research programs. This is not about compliance, but about our desire to protect human research participants, says Mark Yessian, an OIG (Office of the Inspector General) regional inspector general for evaluation and inspections. All parties aim to restore public confidence in biomedical research that has been damaged by deaths and harm due to inadequate research oversight. The question is whether efforts by sponsors and researchers to avoid lawsuits and regulatory problems are imposing excessive controls on R&D and wasting resources. 


The search for fraud and abuse in the clinical research arena is a prime interest of Justice Department attorneys. Assistant U.S. attorney James Sheehan reports that he is focusing more on clinical trial activities as they proliferate in the Philadelphia area.

Misrepresentations in grant applications to NIH or in filings with FDA could generate scrutiny, noted David Hoffman, another assistant U.S. attorney from Philadelphia. Speaking at the Medical Research Summit in Washington, DC in March, Hoffman noted that a study sponsor or investigator could get into trouble by failing to provide  meaningful and full disclosure to patients of research risks and conflicts of interest, failing to report adverse events properly, publishing biased or slanted research results, or falsifying information or records.

Plaintiffs and prosecutors increasingly bring charges involving medical research under the False Claims Act (FCA), which prohibits intentional submission of false claims to the U.S. government. Many of these cases have been initiated by whistle-blowerssuch as nurses at clinical sitesand most have been brought against academic research institutions for fraud related to the misuse of NIH grants. 

Penalties for FCA violations can be  stratospheric, commented attorney Paul Kalb (of Sidley Austin Brown & Wood) at the research summit. He explains that the sponsor of a clinical trial could be liable under FCA if a government health program such as Medicaid pays for a drug or medical product that is approved by FDA based on fraudulent filings with the agency. In December 2000 Johnson & Johnsons LifeScan subsidiary agreed to a $60 million settlement with plaintiffs who argued that FDA would not have approved LifeScans glucose monitoring kit if the company had fully reported adverse events to the agency. The two company whistle-blowers who brought the case collected multimillion-dollar awards and set an example for other concerned insiders. 

Another looming concern for study sponsors is the possibility that payments to physicians for research services could violate the federal antikickback statute. That law imposes heavy penalties on any party that pays someone to induce the purchase of goods or services paid for by a government program. A clinical trial sponsor or CRO could run afoul of this policy if found to pay physicians excessive fees for conducting bogus studies. While preapproval trials that undergo review by FDA and an IRB are unlikely to appear as shams to channel money to heavy prescribers, Kalb notes that the issue can arise with Phase 4 studies. 

Former Justice Department official John Bentivoglio (now with Arnold & Porter) advises pharma companies to look behind their arrangements with clinicians to see whether they are legitimate or could be regarded as a way to transfer payments to influence prescribing. 

A third source of concern for sponsors and investigators is the growing number of trial lawyers filing suits on behalf of individuals harmed through participation in clinical trials. Most of these cases have involved universities and research centers, but CROs or manufacturers that directly oversee subjects in studies could become parties to such suits. The deep pockets of pharmaceutical companies make them ready targets for plaintiffs attorneys.


Many of the cases brought by the Justice Department and private plaintiffs arise from OIG investigations. This investigative arm of the Department of Health and Human Services (HHS) put the spotlight on inadequacies in the nations research oversight system in a June 1998 report documenting the shortcomings of IRB operations. Subsequent OIG studies have raised concerns about human subject recruitment and the proliferation of foreign clinical trials. More recently the OIG has been looking at how well sponsors monitor clinical trials, whether pharma company payments to providers violate the antikickback law, and how human subjects are recruited for clinical trials. 

A new report that is expected in June will evaluate how well clinical trial Web sites convey to the public useful information about research opportunities. The OIG has examined 22 Web sites with 110 clinical trial listings to see if Internet communication provides a vehicle that can help the public understand research issues and promote informed consent, Yessian explained. He noted that many of the clinical trial listings hyped benefits but said little about risks. Some sites touted trials as a way for individuals to obtain experimental drugs or to make money. These shortcomings may spark interest in standards or accreditation of Web sites, as well as requirements for IRB oversight. 


These developments are prompting lawmakers to examine ways to strengthen federal policies governing clinical research. The Senate Health, Education, Labor, and Pensions (HELP) Committee has held hearings on clinical research issues to assist committee chairman Ted Kennedy (Democrat, Massachusetts) and Senator Bill Frist (Republican, Tennessee) develop legislation on the issue. The senators seek to enhance IRB capabilities and to address conflicts of interest and informed consent requirements. 

In the House, Representatives James Greenwood (Republican, Pennsylvania) and Diana DeGette (Democrat,  Colorado) back legislation to apply the Common Rule of 1986 (which governs research funded by federal agencies) to all research, including that which is privately funded. The legislators also may seek to expand the HHS Office of Human Research Protections (OHRP) into a broader agency that would oversee all research involving human participants supported by federal government agencies. Congress currently is focused on several other biomedical research issues,  which are likely to sideline adoption of new laws to enhance human research protections. The legislators have been involved in a heated debate over measures to ban human reproductive cloning, which also could curb research on therapeutic cloning of human embryos. The House and Senate also have to resolve differences in bioterrorism bills approved last year, which include some provisions related to medical research involving toxic agents. 


While Congress studies these issues, FDA is offering new policies to enhance the ability of IRBs to assess study protocols. One plan in the works for more than a year is to require that all IRBs register with the agency. Registration is considered a basic step for FDA and HHS toward getting better information on the range and scope of the IRB community and being able to communicate to that community about policies and requirements.

Another proposal aims to address OIG concerns about IRB shopping by sponsors and investigators. In March, FDA issued a request for comments (through 6 June 2002) on a proposal to require that medical researchers inform IRBs about prior assessments of a protocol by other review boards (Federal Register, Vol. 67, No. 44, p. 10115-6, 6 March 2002). The agency wants to know if sponsors and researchers consider IRB shopping a significant problem and whether it is more common for certain products and situations. If disclosure is warranted, FDA would like suggestions on who should provide information on prior review, how and what should be disclosed, whether a sponsor should reveal both favorable and unfavorable reviews, and whether this information also should be disclosed to FDA. 

One question is whether disclosure is useful without full information on the basis of a prior IRB decisionbut requiring that IRBs explain their reasons for approving or rejecting a study plan would add to their already overburdened agendas. Although the proposal aims to prevent companies from hiding unfavorable IRB decisions, FDA acknowledges that there are situations where it may be appropriate for a sponsor to challenge an IRB decision and seek a  second opinion. In such cases, however, the regulators believe that IRBs should be informed of all the facts.

SIDEBAR: Should subjects decide instead of consent?


The research community is now talking about encouraging informed decision making by research participants, instead of informed consent. Greg Koski, director of the Office of Human Research Protections (OHRP), commented recently that the term informed consent presumes that the individual will give consent; informed decision making, instead, implies that a decision is based on full understanding of the risks involved. 
Jill Wechsler, Washington Editor


Does it seem to you that informed decision making is a more informative way to describe the process of obtaining consent from potential research subjects? Do you think that the term informed consent carries a built-in presumption that individuals will consent?

Do you believe that a new term is desirable to help ensure that subjects are fully informed of their rights and protections? If so, would you choose informed decision making, or would you like to see the clinical research community adopt some other language? 

With your participation and suggestions, this discussion will continue in future issues of 

 Wed like to hear from you by fax (541 984-5250) or email (jganter@advanstar.com). 
Jane Ganter, Editor-in-Chief            

View from Washington

Federal prosecutors target sponsors and clinical investigators who misuse federal funds or violate research requirements while FDA proposes new policies and Congress eyes reforms.

Fraud, Abuse, and Consent

Feature Article

Improving adverse event reporting can lead to improved safety profiles and, consequently, fewer drugs pulled from the market.

Identifying and Documenting Adverse Events at Clinical Study Sites

Meet the EAB

Family man, educator, mentor, athlete--and a man on a quest with Amgen Inc for new and better oncology treatments.

Brian Koziol

A new method, based on hard-earned experience, can help you reduce the risk of protocol inconsistencies and ambiguities during the protocol development process.

Applied Clinical Trials-05-01-2002

Letters to the Editor

Parents for Orphans

Fraud, Abuse, and Consent

Identifying and Documenting Adverse Events at Clinical Study Sites

Brian Koziol

A Model-Based Method for Improving Protocol Quality