For a long time, drug development has been dominated by the urge to find yet a better drug to treat hypertension, hypercholesterolemia or heartburn. Big pharma companies were competing in the major primary care markets. And today, for every indication, more than a handful of blockbuster drugs are available. But now that reimbursement is more of an issue, with many generic products on the market featuring comparable effects, the industry has changed its focus toward more specialized care, like oncology. 

Cancer is still a frightening thought for most people. The search for cancer medicines usually gains the support of the public, even with their rather hostile attitude toward pharmaceutical companies. Until recently, however, the number of drugs developed for cancer treatment was rather limited. Since the discovery of Nitrogen mustard derivates and the anthracyclines, it has been relatively quiet. This may be attributed to the suggestions that cancer drug development is complex. 

The question of whether oncologic drug development is truly different from the development of primary care medicines was discussed during a workshop at the European ACT Summit in the Fall of 2006. The reasons for the relative absence of new oncologic drugs was discussed, based on the statement: Cancer is a rare, lethal, and complex disease that is not profitable for the industry, as drugs require a different development approach. 

 Figure 1. Worldwide lung cancer incidence in men. 			

The incidence of cancer varies enormously across the world. The age-adjusted incidence of breast cancer in China and India is 19 per 100,000 females; that number jumps to 101 in the United States. Similar differences across the world can be found for colorectal and lung cancer. Despite the numbers, incidences of cancer can be considered low when compared to hypertension, heartburn, COPD, and other diseases or conditions. 

The incidence of hypertension is not always well documented, but it is at least 300 per 100,000 persons; the prevalence is thought to be much higher and may even reach 30% in elderly patients.

  Clearly, this condition is of a different magnitude than cancer when compared to the individual types of tumors. Even when adding up the major cancer types like breast, lung, and colon, the total incidence rate per 100,000 persons is below the rate of common diseases and, thus, relatively rare.

 However, when realizing that in many developed countries one in 10 women will be confronted with breast cancer, one cannot call this a rare disease. 

Figure 2. Worldwide female lung cancer incidence. 			

In addition, most cancers have shown a gradual increase in incidence over the past few years, which implies that cancer is a growing problem. 

Cancer is still associated with death by the public. It is probably the most feared message from a physician. The question is whether this is realistic. 

Worldwide, cancer is definitely not the most frequent cause of death. In developing countries infections are responsible for the vast majority of deaths. AIDS, malaria, and other more general infectious diseases kill almost 10 million people a year. In the industrialized world, cardiovascular diseases are the major cause of death. Myocardial infarctions, hypertension, cerebrovascular events, and heart failure kill over 7.5 million people a year.

  In this respect, cancer still plays a relatively minor role. Lung and stomach cancer together cause the death of about 1.5 million people, the other types of cancer considerably less. From a magnitude perspective, cancer is not a lethal disease—but what about the people who actually have it? 

Over the past few decades, cancer survival rates have significantly increased. Overall, more than half of all patients survive more than five years. But there is considerable variation among the different types of cancer. Whereas more than 80% of all patients with skin cancer survive for more than five years, survival is only about 10% for those with esophagus cancer. 

It is important to realize that the increase in cancer survival rates is largely attributable to a few relative frequent cancer types like breast and prostate cancer. For these cancer types, screening programs for early detection have been implemented and there are more treatment opportunities. Compared to other diseases, cancer is still a very serious deadly disease. Fortunately, recent improvements have dramatically improved patient outcomes. 

Some claim that one reason for the relative absence of oncology drugs is that they are not profitable for pharmaceutical companies. But is this claim true? 

In 2001, the best-selling oncology drug was the LHRH analog goserelin, with estimated sales of over $1 billion. It ranked 82 on the top 100 list of best selling drugs, along with docetaxel and oxaliplatin—the only other oncologic drugs on the list. In 2005, docetaxel was ranked 34, and three other oncologic blockbusters made the top 50 list. Many new oncology drugs have recently entered the market, which means increased revenues for the companies.

So, oncology drugs have shown to be beneficial for both patients and industry. Clearly the industry has become aware of this. Almost all major pharmaceutical companies are now focused on oncology drug development. As a result, over 400 new oncology drugs are in clinical development. Still, the number of new oncology drugs that reach the market is relatively modest. This may have to do with the nature of the disease. 

There is no such thing as one disease called cancer. Cancer is just a synonym for a large number of diseases characterized by uncontrolled cell growth. The cause of this loss of control can be very diverse, even within cancers of the same organ. Loss of cell growth control can be caused by loss of control mechanisms that suppress growth. Mutations in so-called tumor suppressor genes can result in loss of growth control, which in turn may result in cancer. On the other hand, cancer may be caused by excessive stimulation of certain pathways. 

Although this may sound relatively easy, the truth is far more complex. Within one patient a tumor often carries cells with different types of deregulations, characterized by different mutations. This may explain why only a percentage of patients benefit from a treatment even though they all have the same cancer type. All this proves that cancer is complex. The question is whether this is the case for other diseases. 

The fact that cancer therapies were toxic and often could not be tolerated forced science to better understand the background and cause of the disease. Molecular biology proved instrumental in this research, which revealed the different signaling pathways that we now know. But it would be naïve to assume that cancer is the only disease in which these genetic defects play a significant role. It was not until very recently, however, that researchers began looking at this correlation. That's because as long as antihypertensive drugs work in the majority of patients without causing bad side effects, their underlying molecular mechanisms are not as interesting. 

Also, in nononcologic therapeutic areas understanding the molecular biology of the disease increases; thus, the chances of developing specific targeted drugs increase. 

All the previous hypotheses have lead to the discussion of drug development in oncology. As mentioned, classical chemotherapeutics require a different approach compared to conventional drugs, but there are more distinct differences. 

Unlike conventional drugs, most oncology drugs cannot be tested in healthy humans. It simply would not be ethical to expose healthy people to highly toxic drugs that could potentially be lethal. Some drugs act on specific targets in cancer cells only or, like aromatase inhibitors, have different pharmacokinetics/pharmacodynamics in cancer patients compared to noncancer patients. This makes it very complicated and even impossible to first test these drugs in healthy volunteers. Therefore, first-in-man trials are usually performed with patients that have no other therapeutic option left. When all available conventional therapies fail, many patients are prepared to take a risk for a small chance of success. 

To limit patients' exposure to doses too low to be effective, only a very small number of patients per cohort are treated. It is always highly frustrating to realize that several patients will likely be exposed to doses too low to be effective; on the other hand, the recent Tegenero incident proves that one cannot be careful enough. That also is the reason why most Phase I and Phase II oncology trials are performed in highly specialized hospitals that are fully equipped and staffed and not in CRO research centers. Conventional drugs are usually tested in healthy volunteers, as toxicity is usually limited and predictable. Safety is still an issue, but treated subjects are in good condition and a specific treatment effect is expected. 

In the era of new, targeted drugs there is yet another dilemma. Oncology drugs act primarily by inhibiting a deregulated pathway, which indirectly leads to cell death. These are the classical cytotoxic drugs. But what is the optimal dose for such drugs? The maximum tolerated dose? The minimum dose that leads to maximum inhibition of the target? 

Drugs like imatinib and sunitinib inhibit their primary target in a nanomolar concentration. Increasing the dose often leads to inhibition of other targets for which these drugs do not as fit well. Sometimes this is favorable, as these targets can also be involved in tumor development. In other cases, increasing the dose only leads to an increase in side effects.

Even though these types of drugs are relatively mild, side effects often do occur at higher doses. Relatively low doses, on the other hand, may lead to early resistance, as lower doses may allow relative insensitive clones of malignant cells to develop into fully resistant ones. Latest opinions tend to favor the minimum dose that maximally inhibits the target. Although not very toxic, these drugs often need to be tested in cancer patients, since the target of the drug is expressed only in these patients. 

Another difference between oncology and conventional drugs is the endpoint of most Phase III trials. Obviously, the most important endpoint is overall survival. In many cases, however, patient prognosis is still rather good, like in early breast cancer. After completion of recruitment, it easily takes more than a decade before results on survival become available. This is unacceptable for patients, and hardly any progress can be made while waiting for the results. 

In addition, survival is heavily influenced by the choice of treatment for recurrences. Relatively ineffective drugs will require effective salvage drugs, and this may obscure the true effects of a drug with regard to survival. Nevertheless, one cannot withhold effective therapy from a patient; so cross-over designs are often used, enabling patients randomized to control arms to switch to the more effective drug once they relapse. Thus, surrogate endpoints like response rate and progression-free survival are commonly accepted, although all parties involved realize the risk involved. The use of response rates is usually confined to Phase II, as it has been shown that the relation to overall survival is not always present. 

Obviously, trials investigating prevention of cardiovascular aspects like myocardial infarction require a long time too, but it's more or less accepted that these drugs are used to counter a symptom that in the end may result in a serious disease. 

The question is whether oncology drugs are really different than drugs used in other therapeutic areas. The answer is not a straightforward "yes" or "no." It must be put in perspective. 

Oncology drugs to a certain extent have served as a kind of role model for other therapeutic areas. It was first in oncology that therapy was aimed at the deregulated cell signaling that leads to the disease. Aromatase inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies have become commonplace in oncology, but in other therapeutic areas the same development paths have been chosen. 

The same is happening with the use of molecular biology techniques. PCR has become an irreplaceable tool in determining the individual patient response, and micro-assays have revealed the diversity of disease subtypes within one type of cancer—which in the future will probably lead to patient tailored therapy. The same is happening in rheumatology, cardiology, and many other therapeutic areas.

Therefore, it is fair to state that oncology has more or less been leading the way in the development of innovative drugs. There is no doubt, however, that within a few years the majority of the differences mentioned in this article will have disappeared, which most likely will be to the benefit of patients. 

is associate director of medical affairs at Celgene BV, Regus La Ligne, Utrechtsestraat 38F, 6811LZ Arnhem, The Netherlands, email: 

 1. J. Staessen, "Epidemiology of Treated and Untreated Hypertension in the Elderly," in 

Handbook of Hypertension Vol. 12, Hypertension in the Elderly

, A. Amery and J. Staesen, eds. (Elsevier, New York, 1989) pp. 320–351. 

 2. C.J. Bulpitt, "Definition, Prevalence and Incidence of Hypertension in the Elderly," in 

, A. Amery and J. Staesen, eds. (Elsevier, New York, 1989) pp. 53–69. 

www.who.int/mediacentre/news/releases/2003/pr27/en/

www.imshealth.com/ims/portal/front/indexC/0,2773,6599_5264_0,00.html

Articles

Feature Article

When it comes to R&D all drugs are not created equal, especially oncologics. And an ACT workshop counts the ways.

Oncology Trials and Drugs: A Unique Therapeutic Areas?

Delivering the right drug to the right patient is a challenge being addressed by researchers and clinicians in a variety of indications. But the challenge is most acute in oncology, due to the generally narrower therapeutic index of oncology drugs. 

The therapeutic advantage of any drug may be lost due to the genetic variability in the metabolism and/or effect of the drug. In oncology, however, researchers must not only deal with somatic polymorphisms but also with polymorphisms, mutations, and genomic expression profiles peculiar to the tumor. Indeed, cancer is characterized by variations in genetic expression, proliferative rates, and survival characteristics of malignant cells compared to normal cells. 

To some, personalized medicine is the same as pharmacogenomics. Pharmacogenomics is the science that examines the inherited variations in genes that dictate drug response and explores the ways these variations can be used to predict whether a patient will have a good response to a drug, a bad response or no response at all. However, one could take a broader view and look at phenotypic manifestations of the genetic variations and recognize that these can be adequate surrogates of actual genetic testing. For example, you could directly test for estrogen receptor expression biochemically or you could assay the gene expression for estrogen receptor expression. 

In general, personalized medicine takes variations between individuals into account in the design of treatment. We are already aware of polymorphisms in the pharmacokinetics of drugs due to variations in the expression of the enzymes responsible for the absorption, distribution, metabolism, and excretion of drugs and their metabolites. For example, there are numerous polymorphisms involved in the cytochrome P450 enzyme system that can affect the handling of drugs and create the potential for drug interactions. Other examples of enzymes and drugs that have influence in the cancer setting include: UGT1A1 (irinotecan), DPD (fluoropyrimidines), and TPMT variants (thioguanine, mercaptopurine). Enzyme activity can be assessed by analyzing the patient's somatic cells and does not require tumor samples. 

Unlike other therapeutic areas however, in oncology this approach can be taken a step further to take into account variations between tumors by analyzing the expression profiles of the malignant cells themselves. In this way, personalized medicine may allow us to further optimize drug effects for both efficacy and toxicity outcomes. However, this often requires sampling of the tumor and sometimes creates problems because the procedure may involve a difficult biopsy or it may involve pain or inconvenience. Doing so in clinical trials may raise ethical concerns, since the results of the testing often do not directly benefit the patient. 

Personalized medicine considerations are often crucial to trials. This is easily illustrated in the case of breast cancer human epidermal growth factor receptor 2 (HER2) status in trials of trastuzumab and lapatinib and in the case of estrogen/progesterone receptors for selective estrogen receptor modulators (SERMS) and aromatase inhibitors. Without the ability to enrich the subjects in these trials, the utility of these agents might still be in question. 

We have reached a point in patient treatment assessment where single nucleotide polymorphisms (SNPs) are sometimes being replaced with genomic signatures using multiple gene expression assays. Since therapeutic response and toxicity to most chemotherapy agents are most likely multigenic traits, we cannot expect the detection of a SNP for a single genetic trait to predict efficacy or toxicity reliably under most circumstances. For example, just as intelligence is inherited through multiple genes, you would need to look at a multigene assay to predict intelligence. In cancer, too, you must look at a profile of genes to predict a relapse after definitive surgery. 

Therefore, we are seeing a revolution in using multigene assays that are capable of representing the complex interplay among multiple polymorphic genes. This is evident by the now accepted Oncotype DX and MammaPrint assays that are being used to plan treatment in breast cancer. 

The Oncotype DX test takes advantage of a reverse transcriptase-polymerase chain reaction assay of 21 prospectively selected genes in paraffin-embedded tumor tissue. The results are capable of determining the likelihood of distant recurrence in tamoxifen-treated, node-negative breast cancer patients. This leads to a recurrence score, which divides patients into low-, intermediate-, and high-risk groups. 

The MammaPrint assay has been approved recently by the FDA for assessing the risk of distant metastasis for female breast cancer patients younger than age 61, with Stage I or II disease, tumor size less than or equal to 5.0 cm, and who are lymph node negative. 

MammaPrint measures the level of gene expression for 70 genes in a biopsy of surgically resected breast cancer tissue. Unlike Oncotype DX, MammaPrint requires fresh tissue. The assay yields a score that indicates whether the patient is in a low-risk or high-risk category for metastatic recurrence of cancer. 

The magic bullet to cure cancer probably does not exist, because cancer is not one disease with one causative mechanism. The same morphologic-appearing tumors may be driven by different pathways. 

We now recognize that similar morphologic tumors are heterogeneous and can perhaps be better classified by their drivers. For example, patients who have triple negative breast cancer are now recognized by different expression profiles and are now classified as basal-like breast tumors (usually ER/PR- and HER2-), and there are separate profiles for "luminal A" (usually ER+/or PR+, HER2-), "luminal B" (usually ER+/or PR+, HER2+) and HER positive breast cancers (HER2+, ER/PR-). Although there is still some overlap, such classifications better enable clinicians to prescribe the most appropriate treatment for a patient: personalized medicine. 

The proper use of personalized medicine in clinical trials requires the use of validated tools. These tools include biomarkers such as hormone receptors, genomic testing, molecular testing, RNA assays, and proteomic tests. The validation process for these tests is a complicated and rigorous process with which an oncology clinical trialist should be acquainted. Table 1 demonstrates some common polymorphisms that are important in oncology. 

The potential benefits of using personalized medicine in clinical trials are enormous. Enriching the sample of subjects, for example, to have a greater likelihood of response or omitting patients with a high risk of toxicity is an obvious advantage that enables a trial to be done more safely with fewer patients and/or within a shorter time. This approach may enable a drug to be registered that otherwise would have been destined to fail if the appropriate patient population was not recognized. In addition, it could potentially rescue previously failed drugs if a newly discovered distinguishing polymorphism is recognized. By restricting the trial to a subgroup of optimal patients, time to registration can be shortened and a broader group of patients tested in the postmarketing period. The approach also allows for observation of long-term toxicity, which would not have been possible if short-term toxicity had led to discontinuation. 

Recognizing population heterogeneity clarifies circumstances where more than one Phase I dose-finding study should be done. For example, a Phase I trial that blends patients who are slow metabolizers with fast metabolizers does not yield the appropriate dose for either population; whereas, a safe dose could be found for each population by running separate Phase I studies. Similar considerations apply when an SNP, genomic profile or surrogate is shown to correlate with therapeutic effect. For example, the pivotal trials for trastuzumab, which required over-expression of HER2, would have required more patients and shown less efficacy if all metastatic breast cancer patients had entered the trials. 

The following are opportunities to use personalized medicine in clinical trials:  					

 Perform dose escalation separately on cohorts with each relevant polymorphism, where AUC, Cmax or other relevant PK parameters are likely to correlate with toxicity. In this way, the dose for each population is maximized for efficacy while toxicity is limited.

 Use this phase as an opportunity to see if enrichment is likely to improve the results of a Phase III trial enough to limit accessibility to this subset of the potential patient population. Other opportunities include:

				–Test the hypothesis that a certain polymorphism might result in greater efficacy and/or less toxicity			

				–Use responders versus nonresponders or tolerant versus intolerant patients as test populations to uncover a genetic signature that might be of value in future trials			

			–Test a known relevant biomarker or imaging study to see if they are predictive of response		

			–Save specimens of somatic tissue and tumor tissue for future testing and back testing		

				–Attempt to salvage a failed trial by using a pharmacogenomic test that was not utilized in the original trial to enrich the population of interest						

. Use data from Phase II trials to develop enrichment criteria for Phase III trials. You can also:

				–Confirm hypotheses generated from data mining the Phase II trial by testing it prospectively in Phase III			

–Prescreen subjects to enrich the population who have favorable predictive pharmacogenomics and avoid those with unfavorable pharmacogenomics to allow the trial to be smaller, faster, and less expensive. 			

The future of personalized medicine will likely parallel the perfection of genome-wide mapping techniques. The large cooperative projects completing the comprehensive SNP and haplotype maps of the human and mouse genomes in the near future will likely accelerate the progress already made after the completion of the human genome project. 

Ultimately, the ability to predict an individual's reaction to a drug before it is prescribed using personalized medicine will improve therapeutic outcomes and will increase both the physician's confidence in prescribing the drug and the patient's confidence in taking it. This, in turn, should encourage the development of new drugs—tested in a like manner—that will possess enhanced efficacy and safety. 

,* DO, is senior medical director for the Americas, oncology, i3 Research, Basking Ridge, NJ, email: 

, MD, PhD, is senior director and section medical director, oncology, the Americas, i3 Research.

*To whom all correspondence should be addressed.

2. Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels http://

www.fda.gov/cder/genomics/genomic_biomarkers_table.htm

3. Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet? http://

www.asheducationbook.org/cgi/content/full/2006/1/111

4. P. Lenehan et al., "Rescuing Drugs Through Personalized Medicine," 

5. C.R. Miller and H.L. McLeod, "Pharmacogenomics of Cancer Chemotherapy-Induced Toxicity," 

6. The Personalized Medicine Coalition, "The Case For Personalized Medicine," http://

www.personalizedmedicinecoalition.org/communications/TheCaseForPersonalizedMedicine_11_13.pdf

7. R. Simon and S.J. Wang, "Use of Genomic Signatures in Therapeutics Development in Oncology and Other Diseases," 

From Phase I to Phase III, there's a part for personalized medicine to play in improving oncology studies.

Opportunities for Personalized Medicine in Cancer Trials

The following Web sites are focused on oncology trials for the professional and/or potential participant. Please note that many pharmaceutical companies currently running trials offer access to them through their own Web sites. In addition, many cancer patient advocacy groups and organizations may have listings for oncology clinical trials on their home pages.—

American Cancer Society/EmergingMed Clinical Trials Matching Service

www.cancer.org/docroot/ETO/content/ETO_6_1X_Clinical_Trials_Matching_Service.asp

This free Clinical Trial Matching and Referral Service is made available to American Cancer Society visitors through a collaboration with EmergingMed. By filling out one questionnaire, patients learn whether they match any trials in the system. The EmergingMed database contains more than 3000 clinical trials for treatment, prevention, and early detection of cancer. 

www.centerwatch.com/cgi-bin/cl.pl?p=patient/studies/cat29.html&h=bcfhd.txt&f=bcfft.txt

This site accesses a database of industry sponsored clinical trials for Breast Cancer. Trials are listed according to U.S. states. Each listing provides information about center names, drug names, and the type of study. Names of international research sites conducting breast cancer clinical trials are also provided. 

This popular site is managed by the oncology research center 

 Inc. and provides numerous resources, including a drug and cancer dictionary, a section for newly diagnosed cancer patients, a free newsletter (SURVIVE), coverage of major medical meetings, and access to clinical trials searchable by cancer type and U.S. location. 

A resource-rich Web site offering cancer-related information for professionals and patients. Features include coverage of over 20 cancer types, access to medical reference texts, live and archived Web casts, continuing education accreditation, multimedia clips, a dose calculator for physicians, online medical journals, a clinical trials search engine, practice guidelines, and disease-specific moderated message boards. Free registration is required to access portions of the Web site. 

A free information service sponsored by Cancer Research UK that provides information on cancer treatments and research along with a search engine that allows users to search clinical trials by type of cancer, trial name or drug. 

TrialCheck is a search tool developed by the Coalition of Cancer Cooperative Groups to assist patients in finding cancer clinical trials. After answering nine simple questions, patients receive a list of cancer trials for which they may be eligible. TrialCheck allows patients to search for cancer clinical trials according to location so that they can find trials close to home. Patients may be updated via email whenever a new cancer clinical trial has been added to their search results. 

Focusing on cancer trials, the site compares patient profile questionnaires to a list of recruitment trials to find a successful match. All profiles are confidential. 

European Organisation for Research and Treatment of Cancer (EORTC)

On this well-designed and easy to navigate Web site, visitors will find a link to the EORTC protocols database, which contains EORTC protocols (classified according to the name of the group undertaking the protocol) as well as protocols from other organizations. The database may be searched by protocol number, group, tumor site, treatment or drug. 

This search site, run by the NIH, allows users to find trials by stage/subtype of cancer and type of trial (e.g., prevention, diagnostic or genetic). It also takes travel into consideration, allowing a distance search by zip code and the option to choose trials from 20 to 500 miles away. 

www.oncolink.upenn.edu/treatment/matching.cfm

EmergingMed's free Cancer Clinical Trial Matching & Referral Service is made available to OncoLink visitors through a collaboration between the University of Pennsylvania Cancer Center and 

. Patients fill out a simple questionnaire and the Trial Matching & Referral Service provides them with matching information about trials taking place at the University of Pennsylvania. 

This is not a clinical trials database, but by giving the company name and drug name, visitors can easily find company Web sites to obtain additional information, including information on cancer clinical trials in progress. 

www.cancer.gov/cancertopics/pdq/cancerdatabase

The National Cancer Institute maintains their PDQ cancer database on this site. This comprehensive resource contains peer-reviewed summaries (updated monthly by six editorial boards) on cancer treatment, screening, prevention, genetics, supportive care, and complementary and alternative medicine. It also features a registry of approximately 2,000 open and 13,000 closed cancer clinical trials from around the world and directories of physicians and other professionals who provide genetics services and cancer care. 

RTOG is a cancer cooperative research group that focuses on radiation therapy. All of the RTOG trials are in the NCI's PDQ database; however, what sets RTOG's offering apart is that they make the entire protocol document for every RTOG trial free to everyone. The protocol document is the complete technical plan for the trial, and includes all the treatment details, a history of the treatment, and references to medical literature. 

www.411cancer.com/ctrials/CTCSearchSteps.jsp?ClinicID=1&Group=domain

 offers visitors a database of industry sponsored cancer trials. A simple three-step process will identify available trials and their locations. The site also offers general information about different types of cancer and cancer management, and has a section on cancer news as well as a provider directory. 

Based in Birmingham, Alabama, this nonprofit organization is dedicated to giving clinical research patients the ability to participate in far-off trials via philanthropic flights. 

Trials Central provides easy, free, and confidential access to listings of clinical trials. Users can search by condition (e.g., cancer diabetes, or HIV) and by type of organization (e.g., hospital, nonprofit, or government). There are also links to other health care information Web sites, including medical dictionaries and published articles. 

Resources

Selected oncology Web sites to assist readers in becoming more informed about cancer and available clinical trials in this therapeutic area.

Internet Resources

The independent review of imaging and clinical data in oncology clinical trials is becoming increasingly important in supporting trial outcomes. The key to designing a successful independent review process centers on prospectively defining the methodology for the review. 

Early in the development of an independent review process, several key documents are generated and signed off as agreements between a sponsor and imaging core lab. These documents include a project plan, Independent Review Charter, and the Investigator Site Manual. 

Through these documents, the sponsor and imaging core lab define a solid review method by describing how the independent review will be performed, the types of reviewers involved, data to be collected from the investigator site, and the assessments the independent reviewers will provide. 

Often the sponsor is able to manage the process by managing the review process documentation. However, while documents may represent an ideal methodology, the review process can break down due to unrealistic expectations, lack of experience and expertise, poor communication, and numerous sustainability issues that can dismantle even the most well-defined independent review. 

As a core document, the project plan describes timelines and budgets, but can also be used to prospectively define the communication and data management plan between the sponsor and imaging core lab. This document also defines how investigator sites will be qualified by the lab and the methodology by which queries from the core lab to the site will be managed. 

One of the ultimate goals of the project plan is to identify any risks that may impact data collection for the independent review and to form a plan for how those risks will be prevented and how any anticipated risks will be mitigated. 

Balancing Act: Stringent vs. Adequate 			

The project plan is heavily influenced by the Independent Review Charter, and ideally these two documents are developed in tandem. The charter defines the overall review process, including the image schedule; types of images and clinical data to be reviewed; the oncology assessment criteria (i.e., RECIST, WHO, IWC, etc.); the types and number of reviewers; the relationship between reviewers (i.e., double reviews with adjudication, single reviews, joint reviews); and reviewer qualifications. 

Sponsors are often eager to have a charter in place for review and approval by regulatory authorities, but many times the key thought leaders involved in designing the charter from the sponsor side, such as the medical lead for the study and the clinical protocol manager, are not aware of the implications of their decisions. One common pitfall in designing an independent review process is dictating stringent data collection activities and review requirements in the charter. 

Early stages of an independent review design are more often focused on medical and regulatory issues rather than operational logistics. As a result, the need for rapid charter development to meet a regulatory deadline excludes other groups such as the sponsor's data management from the charter development process until too late in the process. That is to say, stringent data collection activities and review requirements defined in the charter and project plan are often implemented with little forethought to the overall logistical and financial burden that these stringent requirements place on the trial. Inevitably, many trials that initially mandate very rigorous data collection guidelines are relaxed after a period of prodigious effort to enforce compliance. 

Another core document required early in study start-up is the Investigator Site Manual. This document, distributed by the core lab to investigator sites, has a dual purpose: to establish exact imaging parameters and provide logistical assistance, such as shipping instructions to the site. The Investigator Site Manual typically contains far more detail on the requirements for submitting and collecting images for independent review than the clinical study protocol. Since it provides clear and concise requirements for imaging, the manual is a critical document for investigator sites. 

Training and adequate monitoring are essential to assuring compliance with imaging guidelines and procedures set forth in the site manual. It is of no benefit to develop complex procedures without ensuring the investigator sites have the means and inclination to comply.  

In an ideal situation the core lab will review identical information from the investigator site in the correct sequence. However, since there are two separate data collection activities (by the investigator site and imaging core lab), it is inevitable that data inconsistencies will arise. 

Missing scans, unscheduled imaging visits, discrepant assessment dates, and discrepant exam types (e.g., spiral CTs versus conventional) create numerous problems with comparisons between the two analyses. It is often the case that differences of this sort are only discovered after an investigation into why RECIST assessments, for example, are discrepant. If discovered after an independent review, the data must be corrected and rereviewed—a costly and timely procedure. 

Aside from radiological data, the clinical data utilized during the independent review process consistently becomes a source of complication during reviews. The sponsor's data management group is primarily responsible for receiving and redacting clinical information from the investigator sites for review by the independent radiologists and/or oncologists. In oncology trials where both radiologists and oncologists act as independent reviewers, clinical data can have a significant impact on the review results. Listing this data in the charter is critical for the core lab to know what type of data will be received. However, the type and organization of data often looks feasible during charter development, but very often becomes problematic at the time reviews are set to begin. 

Part of the problem with preparing and organizing clinical data for the independent review process is due to the way in which protocols are written. Study protocols are often developed without much forethought to collecting clinical information that easily facilitates independent review. 

In oncology trials, data such as biopsy or cytology results often have a significant impact on how data are interpreted by the independent reviewers. An oncology dossier of predetermined clinical information from the sponsor's clinical CRF must be presented in a format that is relevant and unbiased. 

Typically, the oncology review component of the review process involves an oncologist reviewing all radiological results in conjunction with a dossier for the subject's case, which covers the entire range of the subject's treatment during the trial. This type of review scenario is generally the preferred option in oncology trials. However, a dossier specified to be sectioned by timepoints/visits within a subject's case may be more scientifically sound than the global oncology dossier for certain disease indications. 

In a chronic lymphocytic leukemia trial, where clinical data plays as large or a larger role than radiological data typically does in a solid tumor study, a dossier organized by timepoint may be more relevant to the clinician interpreting the data than a dossier for the subject's entire case. Similarly, in a melanoma trial, where skin lesion photographs can be reviewed and qualitatively assessed on a timepoint/visit basis, data may be more relevant if it is presented by timepoint. This timepoint by timepoint organization may sound reasonable in theory, but can present a challenge to the data management groups from the sponsor's side that will actually be organizing and exporting the data to the imaging core lab. The net result is that the charter must be amended, usually far too late in the process, because of limitations in the data collection process. 

Data management groups often attempt to format the independent electronic data similar to the investigator data for ease of comparison. However, this traditional method often fails when confronting differences in the two review processes, particularly when there are multiple types of reviewers. For example, a radiologist is required to perform imaging measurements and an oncologist is required to review clinical data, with both reviewers working independently. This differs from the investigator who can fulfill both roles simultaneously. An enlarging pleural effusion, for instance, may instantly be diagnosed as benign by the investigator who has cytology results readily at hand. However, the independent radiologist may be forced to state "unknown" for a response, and defer the matter to the independent oncologist who has access to the clinical information. 

The sponsor's data management group must be cognizant of differences like these and carefully consider the collection and analysis of independent reviewer data. More importantly, they must be a key player in the charter development process, when many of the decisions on data collection are made. 

Although prospectively defining a solid independent review process may appear easy enough with the many key documents in place, there also are sustainability issues that ultimately hinder the process as well. Employee turnover can be detrimental to maintaining timelines and having a historical memory of why certain decisions were made for a trial. A lack of knowledge of the purpose of independent review also routinely leads to a communication break down between the core lab, the sponsor, and the investigator sites. Sponsors must consider the need for some conceptual training on the purpose and ultimate goal of the independent review process. 

At the very least, the protocol may be a vehicle to highlight the existence of an independent imaging review and provide some high-level instruction to investigator sites. 

While there is considerable desire by both the sponsor and the imaging core lab to limit the number of independent reviewers in an effort to control variability, reviewers often leave for unforeseen reasons during the review period. Likewise, study requirements may change, necessitating the addition of extra reviewers late in the review process. 

It makes sense to assume that the ideal independent review process would utilize the skills of the most experienced thought leaders within the therapeutic area as independent reviewers. However, these experts often have very rigorous schedules and limited time to dedicate to independent review activities, which does not offer much flexibility with regard to timeline constraints. It is important during early charter discussions—dominated many times by scientific rather than operation concerns—to strike a balance between reviewer number and availability and the expected reviewer workload. 

Prospectively defining the independent review process through documents such as the project plan, Independent Review Charter, and Investigator Site Manual—among other documents—allows the sponsor to manage the actual review process by managing the documentation. 

The sponsor and imaging core lab must carefully consider the implications of these documents and set realistic expectations for how issues that arise can be easily mitigated. However, regardless of how well-defined the independent review process is, it often breaks down due to a lack of enforcement of the methods defined. Similarly, a process that is too stringent poses the risk of setting unrealistic expectations that the sponsor, investigator sites, and core lab simply cannot meet. 

Poor communication as well as employee and reviewer turnover can also have detrimental effects on even the most well-planned processes. While situations may often not be anticipated, mitigation plans for what to do should issues arise can always be defined. The best defense in ensuring a successful review is to limit the occurrences that can be anticipated and prepare a solid plan for those that cannot be. 

In the long run, prospectively defining how to handle common pitfalls in the independent imaging review process is far easier than trying to develop postreview contingency actions. 

 is program director of the oncology/cardiology group in the medical imaging division of Perceptive Informatics, a PAREXEL company, 900 Chelmsford Street, Suite 309, Lowell, MA 01851.

* BS, MS, MTPW, is a senior medical imaging technical writer in the imaging technical medical writing group at Perceptive Informatics, email: 

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A detailed plan is the key to success. But since even the best laid plans can go awry, a back-up plan is necessary.

Supplements-05-02-2007

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Internet Resources

Effective Management of the Independent Imaging Review Process