Education and debate

Call for a new approach to the process of clinical trials and drug registration

Thomas C Jones, adjunct professor of medicine. 

Cornell University Medical College, New York, NY 10021, USA

Correspondence to: Thomas C Jones, Clinical Research Consultants, Basle 4058, Basle, Switzerland 100767.711{at}compuserve.com

The process of phases I-IV of clinical trials is the cornerstone of the drug registration and regulation process.¹ Yet expanding drug expenses, the slow process of development in critical areas of need, poor worldwide distribution of new therapeutics, and an emerging multibillion dollar industry receiving finances for clinical trials as a part of healthcare delivery, indicate that the process needs revision. Recent changes in testing by clinical trials, different methods of supervision of drug development by pharmaceutical companies, and new methods for the monitoring of drug safety suggest a direction for this revision. A fresh approach is proposed (see boxes, p 921). This article reviews the basis for considering this new approach.

	Recent changes in the process of phases I-IV of drug development

The initial goal of clinical trials for drug registration was that a new drug treatment must be safer and more effective than no treatment for a specific disease. A plan to achieve this goal was outlined in the United States by the Kefauver-Harris Drug Amendments, approved in 1962.² The box on p 922 describes phases I-IV that have evolved.¹ This has become the central part of drug registration both by the Food and Drug Administration in the United States³ and by the European Commission.⁴

	Improvements in the study design of phases I and II

In the past, phase I and II studies were often open label and non-randomised and done in small numbers of patients. As a result, neither efficacy nor safety data were considered reliable. Randomised, double blind, placebo controlled phase III trials were therefore considered justified and ethical.³ During the past decade, however, the importance of properly designed early trials (phases I and II) has led to dramatic changes in their design.⁵ These changes have included both proper randomised, double blinded designs and increased sample sizes. Although there is disagreement about how best to use data from phase II in the present process of phases I-III,⁶ there is little doubt concerning the high level of data available by the end of phase II. Because of the extensive data available, many phase III and virtually all phase IV placebo controlled trials are rendered redundant and potentially unethical.

	Mistakes in study design versus drug inefficacy in phase III

Mistakes in the design of a drug trial are often made by designers in preparing and conducting phase III clinical trials. These mistakes are usually reported as drug failure rather than poor pharmaceutical company expertise, excessive marketing influence, regulatory micromanagement, or improper patient enrolment and follow up. Approaches in the design of phase III clinical trials have also led to incorrect recommendations regarding drug dose or duration in trials considered to have been successful. Examples of mistakes include requirements for inappropriate end points for evaluating the drug, study of a single drug dose or treatment, incomplete data for calculating sample sizes, over enthusiastic reports of occurrence rates of diseases by potential study centres, inadequate attention to patient inclusion or exclusion criteria, and incomplete follow up. The assumption has been that these are problems for the pharmaceutical companies to solvethe regulatory role is simply to identify them and reject failed studies. This is false. It is a problem created by the process of clinical trials, and it should be solved by the entire healthcare community.

	Ethical problems with informed consent in phase III

Issues of ethics and possible conflicts of interest have been noted recently in studies done in developing countries,⁷ and potential conflicts of interest have been identified in the conduct of studies in the United States.^8-12 The ethical issues raised contribute to the global concern that activities carried out during the later stages (phases III and IV) of the present process of clinical trials are balancing on the edge of inappropriate activities, both by academic medical centres¹² and during physician-patient interactions. ^{6 11} These issues have been addressed by regulatory authorities in Europe by their request for comparative phase III trials of marketed drugs. But because comparative drug trials tend to require larger numbers of patients, as the goal is often to show equivalence, global pharmaceutical companies have sought approval in the United States with placebo controlled trials, then have used these to register in Europe. As long as authorities require or accept these trials the ethical problem remains.

	Expansion of the questions asked during clinical trials

The initial goals of drug evaluation have been modified to include new questions directed at goals other than drug efficacy and safety. For example, testing a drug in a population representing the "real world setting" has become a major basis for phase III trials. This step has so altered the evaluation of the drug itself that potentially useful drugsusually those with partial effects in a complex disease processwill never be made available. For example, in a recent review, over 75 different potential therapeutic agents were listed for use in the treatment of septic shock.¹³ None will be available because of the heterogeneity of patients with septic shock from the "real world" enrolled in phase III trials.

Other new questions that have been asked are "how should a physician be advised to use the drug in her or his medical practice?" and "is the drug better or similar to a drug already available?" Pharmaceutical companies have asked for financial risk and benefit analyses and quality of life studies to accomplish successful registration and marketing of a drug. Obtaining answers to these questions has become a part of the phase III process of clinical trials. Clinical trials have moved from a role in drug assessment to physician education and competitive marketing. These changes have required a new management system dominated by calculations of sample size, goals for patient recruitment to accomplish large clinical trials, and the emergence of a new industry to organise clinical trials. ^{11 12 14} In retrospect it must be asked whether these are efficient and appropriate changes to accomplish better drug assessment and improved health care.¹⁵

	Changes in supervision of drug development by pharmaceutical companies

Another major event has been the change in the management structure of pharmaceutical companies since the present structure of clinical trials began. ^{16 17} The change in supervision of the drug development process by pharmaceutical corporations occurred, in part, because of regulatory requirements and because of corporate, marketing, and legal forces that emerged concurrently. For example, pharmaceutical companies began instituting a careful review of phase transitions during drug development, including a full summary of data and scientific presentation at the end of phase II within the company, and, in some cases, to regulatory agencies such as the Food and Drug Administration. This change has created ethical issues that have been largely ignored. With all the data to hand it is very difficult to defend the presentation of an informed consent form to a patient about to be enrolled in a phase III placebo controlled trial.

	Safety assessment during phase III studies and the emergence of post marketing surveillance

Because safety data about common, severe, and dose related adverse events are now fully collected and reviewed at the end of phase II, very limited new information about the drug is identified in phase III. It has been stated that uncommon adverse events, such as those occurring at a frequency of less than 1 per 100 patients, cannot be identified in phases I-III.¹ Rare adverse events emerge only during post marketing surveillance. Proper evaluation of a drug's safety requires tens of thousands of treated patients and can only be done by careful post marketing surveillance.¹⁸ This type of surveillance has been particularly successful in the United Kingdom where the government's "yellow card" system of reporting all drug related adverse events has provided the healthcare community with an accurate picture of a drug's safety profile. Academic medical centres have developed effective research units for drug surveillance, and pharmaceutical companies now catalogue annually the pattern of adverse events of any marketed drug. These initiatives seem to be far more relevant to understanding the safety of drugs than are expanded numbers of phase III trials. What can be done to redirect the clinical process in a more efficient and financially reasonable direction?

	Suggestions for new approaches to drug registration

Assess the safety data from phase II and phase III clinical trials
The issue of whether new safety and efficacy data emerges during phase III clinical trials needs to be further studied. Comparison of profiles of adverse events at the end of phase II with those at the end of phase III would provide this information. Data from the end of phase II are available in the files of pharmaceutical companies and regulatory agencies, but this information is not usually, or systematically, available in the literature. By removing the need for safety data from phase III trials, then removing the use of placebo controlled phase III and phase IV trials altogether, most of the ethical and conflict of interest issues would disappear. Needless to say, careful review of all clinical trials by properly constituted ethics committees must continue. What then would be a substitute for the present reliance on phase III trials for drug registration?

Recognise the need for flexibility for drug development
Firstly, we must agree that different types of drugs and different diseases require entirely different approaches to clinical trials. It is illogical that a protective vaccine or a modulator of immunity to cancer would follow the same pathway for registration as a drug for treating constipation, sepsis, or dermatitis. Drugs developed on a basis of sound theoretical models and animal trials should not follow the same route as a compound without such a basis. Therefore flexibility in drug assessment would be a required part of the new process.

Establish an interactive group for review of drugs
To decide how best to proceed after evaluating these studies the areas listed in the box would be assessed by appropriate experts within the regulatory agency in consultation with experts both within and outside the pharmaceutical company. This medical advisory panel could be similar to that recently recommended to evaluate the pharmaceutical industry.¹⁹

Gain information on drugs after the licensing process
Use of the drug in patient populations from the "real world" and comparisons to similar available drugs would be left to the judgment of investigators and the goals of marketing departments after the drug is licensed. The main vehicle for drug safety would be the expansion of post marketing surveillance systems. Carefully conducted observational studies could be used to answer emerging questions about efficacy. ^{21 22} A new role for experts within pharmaceutical companies would be to ensure that all data on dose ranging safety and efficacy done in phases I and II were published and that complete data listings were available on the internet. This would require new resources within pharmaceutical companies, but the activity would be far more useful to the healthcare process than is the case with the present phase III trials. The direction outlined in this article could provide needed vigour and innovation in drug development, faster access to advances in medical practice, and reasonable healthcare costs.

	Footnotes

   Funding: The operating budget of Clinical Research Consultants helped fund the preparation of this article.

Competing interests: The author has been consulted by various pharmaceutical companies to evaluate study designs before their initiation and before their presentation to regulatory agencies.

	References

1.	Nies AS. Principles of therapeutics. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. Oxford: Pergamon Press, 1990:62-83.
2.	Lasagna L. Congress, the FDA, and new drug development: before and after 1962. Perspect Biol Med 1989; 32: 322-343[Medline].
3.	Food and Drug Administration, Center for Drug Evaluation and Research, Guideline Documents. fda.gov/cder/guidance (accessed Nov 15 2000).
4.	International Conference on Harmonization. ICH-Guidelines. eudra.org/humandocs/humans/ich.htm (accessed Nov 15 2000).
5.	Thall PF, Simon RM. Recent developments in the design of phase II clinical trials. Cancer Treatment Res 1995; 75: 49-71[Medline].
6.	Fazzari M, Heller G, Scher HI. The Phase II/III transition. Toward the proof of efficacy in cancer clinical trials. Control Clin Trials 2000; 21: 360-368[CrossRef][Medline].
7.	Lurie P, Wolf SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med 1997; 337: 853-855[Free Full Text].
8.	Eichenwald K, Kolata G. Drug trials hide conflicts for doctors. New York Times 1999;May 16.
9.	Bradley SG. Conflict of interest. In: Marcina FL, ed. Scientific integrity. Washington DC: ASM Press, 1995:161-188.
10.	Jones TC. Ethical issues regarding randomized, placebo-controlled clinical trials and their publication in medical journals. Braz J Inf Dis 1997; 1: 266-271[Medline].
11.	Bohenheimer T. Uneasy alliancesclinical investigators and the pharmaceutical industry. N Engl J Med 2000; 342: 1539-1544[Free Full Text].
12.	Angell M. Is academic medicine for sale? N Engl J Med 2000; 342: 1516-1518[Free Full Text].
13.	Lynn WA, Cohen J. Adjunctive therapy for septic shock: a review of experimental approaches. Clin Inf Dis 1995; 20: 143-158[Medline].
14.	Weihrauch TR. Design, management and costs of multinational trials. Eur J Clin Res 1994; 6: 26-36.
15.	Hansen RW. FDA regulation of the pharmaceutical industry. In: Higgs R, ed. Hazardous to our health? FDA regulation of health care products. Oakland, CA: Independent Institute, 1995:13-27.
16.	Burley DM. The pharmaceutical physician and the company medical department. In: Burley DM, Binns TB, eds. Pharmaceutical medicine. London: Edward Arnold, 1985:260-282.
17.	Struck M-M. Biopharmaceutical success rates and development times. Biotechnology 1994; 12: 674-677[Medline].
18.	Dunn N, Mann RD. Prescription-event and other forms of epidemiological monitoring of side-effects in the UK. Clin Exp Allergy 1999; suppl 3: 217-239[CrossRef].
19.	Angell M. The pharmaceutical industryto whom is it accountable? N Engl J Med 2000:1902-4.
20.	Jones TC, Badaro R. Incentives and penalties in health care: getting the best from pharmaceutical development. Braz J Inf Dis 1998; 2: 37-42[Medline].
21.	Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research design. N Engl J Med 2000; 342: 1887-1892[Abstract/Free Full Text].
22.	Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000; 342: 1878-1886[Abstract/Free Full Text].

(Accepted 27 November 2000)