Role of Academic Clinical Trials Groups in Global Drug Development

Prof Elizabeth Eisenhauer National Cancer Institute of Canada Clinical Trials Group Queen's University Kingston, Canada

Cancer Drug Development

Cancer drug development is traditionally an orderly passage of a new agent or therapeutic strategy through a series of trials, beginning with phase I dose-seeking trials and ending with submission for marketing approval (Table 1). Historically, in North America, the USA National Cancer Institute (NCI) was the major sponsor of early clinical trials. Subsequently, randomised trials were performed both by cooperative groups and, to a lesser extent, the pharmaceutical industry. However, this environment has changed in a number of ways.

In the past, the source of new agents was mainly non-commercial groups such as the NCI or academic units plus a few major pharmaceutical companies. Currently, however, cancer drug discovery is being undertaken by all major pharmaceutical companies as well as by start-up biotechnology firms, while non-commercial groups have a less prominent role.

Other relevant changes include 'simultaneous' analogue development, by which multiple agents affecting the same target are entering clinical studies at the same time. This leads to increased industry competition, greater competition for patient/physician resources, and a drive for cost-effective clinical trials.

Table 1. Passage of a new agent or therapeutic strategy to clinical use.

Academic and Pharmaceutical Industry-Sponsored Trials

The primary drivers for academics involved in this area are to unravel the biology of cancer, identify new treatments that reduce the burden of cancer suffering, define who requires treatment, and publish in peer-reviewed journals. However, the driving force for the pharmaceutical industry is somewhat different as, primarily, companies must return value to their shareholders. To do that, they must provide useful new products for patients by taking a compound from research, turning it into a drug, and achieving regulatory approval. Further, companies are motivated to increase market share when competitive products are available.

In academia, there is a difficult balancing act between patient care, teaching, and research. Within industry, there are different pressures of time, cost, and risk. However, there is an overlap of interests between academia and industry, notably with regard to the conduct of trials of new agents (Figure 1).

Due to the significant overlap between the pharmaceutical industry and academia with regard to their interest in performing phase I, II and III trials of novel agents, it is logical to consider why the pharmaceutical industry should not simply undertake the responsibility for the conduct and coordination of all these trials. Prof Eisenhauer suggested there were problems with devolving to industry the entire responsibility for drug development. These problems are summarized in 4 different areas.

Figure 1. Overlap of interests between academia and the pharmaceutical industry.

Trial Design and Hypothesis
In general, the agenda for the pharmaceutical industry is to develop the fastest strategy to place a new agent on the market. Industry-coordinated trials may therefore be designed to address this in the first instance rather than to address what the greatest need may be. However, the academic agenda tends to focus on trials that have the greatest impact on disease. Thus, there may be conflict between the industry and academia in deciding which trials should be performed.

Number of Studies
The pharmaceutical industry tends to have a focussed development plan, since the available resources are limited. Thus, the total number of trials that can be resourced by the industry is limited. This problem is most acute for new biotech companies where there is no income from sales and the only income is from investment, so only a few trials would be possible.

Publication Restrictions
In an article published in the New England Journal of Medicine as well as in other major medical journals last year, Davidoff et al pointed out that "Investigators may have little or no input into trial design, no access to raw data, and limited participation in data interpretation. These terms are draconian for self-respecting scientists, but many have accepted them because they know if they do not the sponsor will find someone else who will. And, unfortunately, even when an investigator has had substantial input into trial design and data interpretation, the results of the finished trial may be buried rather than published if they are unfavourable to the sponsor's product."¹ The position taken by these authors may be extreme, but it does represent a view based upon the experience of some investigators working with industry-sponsored studies.

These authors made some recommendations regarding the criteria for accepting articles for publication from industry-sponsored studies, as follows:

• contractual agreements must allow investigators the right to examine the data
• the sponsor must impose no impediment to the publication of the studies full results

Further, the authors indicated that changes reflecting these recommendations would be made to the Uniform requirements of manuscripts submitted to biomedical journals.²

Access to Data
Industry-sponsored trials use data collection methods that give them complete control of the database (directly or through contract research organisations). Investigators may see the data output, but generally cannot query the data, raising the possibility that interpretation of results may be biased. Finally, under theses circumstances, there is little opportunity for investigators to use the data for subsequent exploratory analyses that may generate new hypotheses for study.

Academic Clinical Trials Groups
Viewpoint: Solutions to Problems

The definition of an academic clinical trials group (CTG) is a network of investigators and institutions who have agreed to collaborate. They are associated with a central operations and statistical office and are formally organised to perform multicentre clinical trials. The core funding comes from a not-for-profit source (either a charity or government). The NCIC CTG is one example of an academic CTG enagaged in clinical cancer research studies.

Properly structured CTGs can provide solutions to all of the 4 problems cited above. Academic CTGs can design trials and/or have input into refining the design of studies developed by industry. They can conduct a complementary cadre of studies to those conducted by industry, which increases the total number of studies. Through strong contractual arrangements, CTGs can hold the database for their studies and can guarantee the publication rights of their investigators. Some specific examples of each of these points follow.

Trial Design and Hypothesis
Trial Design and Hypothesis Examples of trials designed by CTGs that have had an impact include Gynecologic Oncology Group (GOG) 111, ³ National Cancer Institute of Canada (NCIC) CTG MA.5, ⁴ and the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) gastrointestinal stromal tumours (GIST) study.⁵ All of these trials have led (or will lead) to a new indication for approval.

The GOG 111 study randomised patients with sub-optimal stage III/IV ovarian cancer to receive standard care with cisplatin and cyclophosphamide or cisplatin and paclitaxel.³ When this trial was first proposed, some were of the opinion that substituting an old drug with a new one, rather than adding the new drug to the regimen, was a high-risk strategy for showing improvement in outcome. However, this trial did show a highly significant survival advantage for the paclitaxel combination. This was a landmark trial that led to front-line approval for paclitaxel in ovarian cancer.

In the NCIC CTG MA.5 trial, Levine et al were interested in exploring the effect of substituting methotrexate with high-dose epirubicin in the standard adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) regimen for breast cancer.⁴ This hypothesis was tested in a randomised trial performed in 716 premenopausal women with node-positive breast cancer (Table 2).⁴ There was a significant improvement in disease-free survival and a borderline significant improvement in overall survival with the epirubicin-containing regimen, CEF (cyclophosphamide, epirubicin, fluorouracil). These data, plus those of other investigators, were part of the submission that led to Food and Drug Administration (FDA) approval for epirubicin in the USA.

Table 2. Protocol for the National Cancer Institute of Canada Clinical Trials Group MA.5 trial.

The EORTC has an active Soft Tissue and Bone Sarcoma Group who have conducted a phase I trial into GI stromal tumours using STI571. ⁵ Data presented at the American Society of Clinical Oncology Annual Meeting in 2001 show that this highly resistant tumour was exhibiting dramatic responses to this novel targeted therapy. This spawned a series of subsequent studies performed by cooperative groups in Europe and North America.

Number of Studies
When interested in performing trials of a novel drug, the NCIC CTG will approach the relevant pharmaceutical com-pany with the proposal(s) for trials. Some of these proposals may be the same as the ideas of the company, but others may not be on their list. The CTG may then offer to expand the number of studies originally planned by the company by pooling resources. A number of studies performed by the NCIC CTG fall into this type of category, for example studies of interest to the academic investigators of the CTG but not necessarily of the company involved. There are many examples of this increase in the number of studies in the development plan of a new agent when CTGs are involved in the process.

Publication Restrictions and Access to Data
It is possible to make the publication rights clear in contracts between academic CTGs and the pharmaceutical industry, thus avoiding non-publication or delays in publication of full study results. Regarding access to data, when a CTG collaborates with industry, in general it is desirable that the CTG should hold the database. The company may receive a copy of the database and own rights to the data, which is needed for preparation of annual reports and submissions to regulatory agencies, amongst other things.

The company may also hold their own (separate) database by entering the trial data themselves, but this must be reconciled with the CTG database. It is important that the company and the CTG agree to methods by which data is queried and cleaned at the outset of the study to avoid any problems at the end of the process.

As an example, the NCIC CTG will not participate in any trial with pharmaceutical company sponsorship unless

• the academic group (NCIC CTG or another similar group) holds the database
  
• the academic group conducts the analysis of data for presentation and publication.

Pharmaceutical Industry Viewpoint

The pharmaceutical industry may raise some objections to some of these ideas and comments. Companies may be concerned about loss of control if the database is held by a CTG and if the primary analysis for publication is conducted by a CTG rather than themselves. However, the recommendations of Davidoff et al suggest that total control of data by the industry may no longer be widely acceptable. The concept of the academic group holding the database may in fact be advantageous to a company in terms of the credibility of the results to the medical community. Joint planning of database content by the group and the company should solve most issues relating to the database.

Secondly, working with CTGs will inevitably increase the amount of bureaucracy involved in trial conduct since 2, rather than only 1, organisations are involved. Ideally, both the company and the CTG should work together to reduce the burden of bureaucracy. Less sequential review and more simultaneous review should help to overcome this problem.

Thirdly, it is often cited that CTG standard operating procedures are not FDA (or ICH GCP) compliant. However, this concern on the part of a company may relate more to internal interpretation of these standards or guidelines rather than to the procedures themselves. However, if a CTG is not compliant with such standards, then they must undertake the changes necessary to become compliant. The ultimate test of any CTG's credibility is the quality of its data and how it stands up to independent review.

Fourthly, companies may worry that involvement of CTGs will substantially slow down the development process. It is often true that CTGs move slowly, and this should be addressed by their becoming more efficient if they are to be competitive. For example, expedited approval of early phase I and II trials should be possible, and creating and using templates to develop study protocols efficiently is a useful strategy. Rapid trial development and completion can be achieved if the industry and CTGs plan carefully and realistically together, and are careful of imposing deadlines that cannot be met.

Finally, pharmaceutical industry may have intellectual property (IP) concerns in working with another organisation. These can be dealt with at the level of the contract. Universities and others with signing authority may require some guidance as to what the situation is with patented compounds so as not to create unrealistic expectations regarding IP ownership.

Global Cancer Drug Development in 2002: Summary

There are currently large numbers of novel agents affecting a multitude of targets relevant to cancer. Preformed Academic Clinical Trials Groups exist in North America, Europe, and Asia and are eager to access new agents. Patients are increasingly better informed and want access to new treatments. At the same time, the pharmaceutical industry is under increasing pressure to achieve early results and registration.

Thus it seems evident that academic CTGs offer an important opportunity for investigators, patients, and the pharmaceutical industry to play a vital role in future drug development. CTGs can contribute to trial design and increase the number of trials conducted, thus enhancing the scientific agenda and increasing patient access. By holding the trial database, CTGs may render the trial more credible for all concerned. Finally, CTGs can contribute in important ways by identifying the efficacy of new cancer treatments.

References

1. Davidoff F, DeAngelis CD, Drazen JM, et al. Sponsorship, authorship, and accountability. N Engl J Med 2001;345:825-826.
2. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. J Am Med Assoc 1997;336:309-315.
3. McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6.
4. Levine MN, Bramwell VH, Pritchard KI, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998;16:2651-2658.
5. van Oosterom AT, Judson I, Verweij J, et al. STI 571, an active drug in metastatic gastrointestinal stromal tumors (GIST), an EORTC phase I study [abstract]. Proc Am Soc Clin Oncol 2001;20:1a.