Therapeutic Innovation & Regulatory Science

Prior to the 1980s, little was known publicly about how pharmaceutical, biotechnology, or medical device companies (ie, the industry) conducted clinical trials or how they managed the dissemination of the outcome of these trials. Pressure from patient advocacy groups helped bring about the AIDS Clinical Trials Information System and Section 113 of the Food and Drug Administration Modernization Act, which provided for a clinical trials registry for serious and life-threatening conditions known as ClinicalTrials.gov. Additional interest by the International Committee of Medical Journal Editors, the World Health Organization, and others challenged the US Congress to pass the Food and Drug Administration Amendments Act (FDAAA), which was signed into law in 2007. This article explores the negative and positive unintended consequences that befell the pharmaceutical, biotechnology, and medical device industries, patient advocacy organizations, and medical/scientific journals following the implementation of FDAAA.

Clinical trial disclosure has received much international attention. The US Congress has enacted the Food and Drug Administration Amendments Act of 2007 (FDAAA), also known as Public Law 110-85. Section 801 of FDAAA requires public registration of new or ongoing clinical trials and disclosure of results for completed clinical trials on the public database ClinicalTrials.gov. FDAAA has provisions for proof of compliance and authorizes penalties for noncompliance; several phases will be implemented over 3 years and completed by 2010.

In the European Union (EU), the European Parliament enacted the Clinical Trials Directive (Directive 2001/20/EC of April 4, 2001), which governs public access to information on clinical trials in the European Community. Article 11 of the Clinical Trials Directive, enforced by the European Medicines Agency (EMEA), deals with the exchange of information among the EU member states. In some cases, it also deals with the countries of the European Economic Area. The directive is accompanied by two regulations; one refers to clinical trials in general, and the other applies specifically to trials in the pediatric population. These regulations describe how some of the protocol and results information in the EudraCT database at EMEA will be automatically released to the public through the EudraPharm database. The public release is planned for 2010 and 2011.

Requirements for clinical trials disclosure have also been established at the national level in several countries. A summary is presented here of the key global requirements for public disclosure of clinical trial information on drugs, biologics, and medical devices, with a brief overview on the position of various stakeholders involved in this important and evolving topic.

Clinical trial disclosure initiatives have slowly emerged in response to stakeholder and public response to questions of safety and efficacy of drugs and perceived secrecy by the pharmaceutical industry. Originally, clinical trial disclosure and transparency activities focused upon therapeutic compounds of interest to seriously ill patients who hoped that by participating in clinical trials, they might contribute to the development of effective drug treatments for their disease and to the common good. Over the years, additional stakeholders have entered the discussion, causing an expansion in the transparency requirements, from meeting patients' and their physicians' needs for information to meeting researcher, insurer, and legislator needs. This article provides a brief look at the history of the clinical trial disclosure initiative as it has evolved worldwide.

The Food and Drug Administration Amendments Act (FDAAA) created new requirements regarding registration of clinical trials and the posting of trial results in a public database, ClinicalTrials.gov. Some of the new requirements have already gone into effect while others must be established by rulemaking in the coming years. Specifically, FDAAA Title VIII requires that regulations must be issued by September 27, 2010, to expand ClinicalTrials.gov.

The Biotechnology Industry Organization's Clinical Committee and the Drug Information Association Clinical Trials Registry/Results Database Working Group conducted a questionnaire regarding ClinicalTrials.gov to better understand companies' and institutions' experiences with the registry, as well as policies and procedures regarding trial registration and results. In this article, we provide the comprehensive results of the questionnaire. Federal and state policymakers, as well as other organizations, may find sponsor results helpful as they develop new clinical trial registration and reporting policies.

Defining a clinical trial registration and results disclosure (CTR/RD) business process is challenged by a dynamic set of expectations to be met. External stakeholder groups have differing expectations of and uses for disclosed information about clinical trials. Regulations in the United States and internationally continue to evolve and emerge. A growing number of portals offering varying information about the same studies have a profound effect on the volume of work and create pressure to keep information across portals consistent. This article focuses on the challenges of changing and improving CTR/RD database processes in response to new expectations, new regulations, and imperatives for increased efficiency. Some keys for success are offered.

In hospitals and clinics around the world, ordinary people place their health and their very lives in the hands of researchers who test new experimental drugs for safety and effectiveness. The public and legislators worldwide have expressed increasing interest in understanding how clinical trials are conducted and the results of those trials. The list of stakeholders has grown substantially in recent years to include medical and scientific academia, government agencies, regulatory authorities, and advocacy groups. Quite logically, stakeholders' interests have shifted slightly from the registration of clinical trial protocol information to the posting of clinical trial results upon trial completion. Protocol registration and results reporting requirements are staggering, diverse, and complex. This article provides a look at industry experience with the operational challenges of clinical trial registries and results databases that the pharmaceutical, medical device, and biotechnology industry, and academia face when providing clinical trial information.

In this age of mandated clinical trial registries and results databases, pharmaceutical, biotechnology, and medical device companies struggle to disseminate information about protocol and trial results in ways that patients can easily understand. Patient advocacy groups are seldom consulted when clinical trial protocols are developed or when trial results are released, yet these groups represent tens of thousands of patients with diseases and disorders. In fact, patient advocacy groups were key drivers in the passage of the Food and Drug Administration Amendments Act (Section 113), which fostered in the era of transparency. This article highlights how advocacy organizations function as a direct conduit to specialized patient populations and how these groups can provide a communication channel to reach thousands of potential clinical trial participants.

Recent changes in US legal obligations to disclose clinical trial results have created confounding challenges for sponsors of clinical trials and for editors of medical and scientific journals with policies prohibiting prepublication of clinical trial data. For nearly two centuries, peer-reviewed manuscripts have served as the primary means of scientific communication. In recent years, however, criticisms of the delay in publishing clinical trial data and publication bias have increased. Prominent journal editors have strongly suggested that online clinical trial registration prior to study conduct would mitigate these concerns. With the recent addition of legally mandated clinical trial results disclosure within specified time limits on ClinicalTrials.gov, the very registries and results databases once used in part to address publication bias may now actually jeopardize the ability to publish the results in peer-reviewed medical journals. Both types of disclosure (ie, posting in results databases and publishing traditional manuscripts) play important roles in the dissemination of clinical trial results, but current requirements now test the medical journals' policies, which effectively reserve the right of the journal to be the primary source for clinical trial data. As sponsors struggle to meet the legal clinical trial disclosure requirements while attempting to get manuscripts published, it is not clear at this time what the final impact will be on sponsors, journals, investigators, health care providers, the media, and the ultimate customer, the patient.

In recent years an explosion has occurred in the disclosure of clinical trial information through clinical trial registries, partly driven by legislative demands and the requirement by a group of pharmaceutical journals for increased transparency. As a consequence, a large amount of information is now available to the general public and health care providers. In complying with the disclosure requirements, different pharmaceutical companies have chosen different approaches in providing clinical trial information. We conducted a survey among a sample of pharmaceutical companies of varying size to determine their views on the current situation, the challenges they face, and the future of the clinical trial disclosure initiative.

Key learnings were that, in their view, transparency has improved substantially, but more so for the scientific community than for the patient. Patient awareness is thought to be relatively low. The increasing demands of legislation cause challenges for companies both in interpretation and in resource requirements, and it was thought this may cause the industry and the whole initiative to lose sight of the original aim, which was to improve transparency for the general public and the patient. Particular challenges mentioned include the new requirements for clinical trial data disclosure and the provision of lay summaries, the proliferation of registries with the associated potential confusion for patients, and the increasing complexity of legislation. Overall, survey respondents concluded that while much has been achieved, more remains to be done, and that patient needs should take priority.

The diversity of pharmaceutical regulatory requirements makes marketing new drugs a very complex and costly process that delays public access to innovative and essential drugs. In recent years, the pharmaceutical industry has become increasingly multinational, taking advantage of the growing opportunities in the rapidly expanding new markets in Asia, Latin America, the Middle East, and Africa. This globalization trend created the need for a new strategic approach to pharmaceutical regulations, leading to more international cooperation and harmonization. Globalization of pharmaceutical regulatory standards has become a necessity and a goal for many groups of neighboring countries in several regions of the world to reduce unnecessary and duplicative requirements, rationalize time and costs, and create a transparent regulatory process that improves access to medicines. Regional harmonization is characterized by a number of initiatives driven mainly by common economical and social needs and supported by global organizations such as WHO and ICH. This article provides an introduction to the major global and regional drug regulatory harmonization initiatives. These initiatives are at different stages of development and maturity, those including the more established countries being at more advanced stages than the less-resourced ones.

Modern drug development requires an efficient clinical development program to have a reasonable chance of successfully leading to the submission of the therapy, given that the therapy is effective, or to early stopping if this is not the case. Clinical trials and programs should be designed to effectively support this final goal. Currently, the statistical planning in drug development is based on parts of a clinical program in isolation, conditioned on one fixed setting, focusing on sample size calculation or simple design questions. There is, however, an increasing demand for a clinical program optimization and acceleration as well as an unconditional evaluation of relative program efficiency, robustness, and validity. The complexity of the development process, however, often does not allow for simple solutions, frequently requiring computer simulations to support these assessments.

We propose a general framework for comparing competing options for clinical programs, trial designs, and analysis methods as a basis for decision making and to facilitate the internal and external dialogue with key stakeholders. The final decision making ultimately needs to factor in quantitative aspects as well as additional qualitative dimensions such as logistic feasibility, regulatory acceptance, and so on. A terminology is introduce that clearly describes the different aspects of such a framework, the range of underlying assumptions, the competing options, and the metrics that are used to assess and compare these options.

Three specific case studies are presented that illustrate these concepts at three different levels: program planning, trial design, and analysis methods.

The European Pharmaceutical Forum (EPF) issued “good practice” recommendations on the need to identify and reward valuable innovation. We investigated the compliance of the Belgian reimbursement procedure with the specific EPF recommendations by analyzing all 110 submissions for added therapeutic value (ATV) in the period 2002–2007. Prior to the reimbursement decision, a relative assessment of the therapeutic value was done with a binary outcome (ATV granted or refused).

Overall, ATV was granted for 61 submissions (55%) or 10 compounds per year. Because this number is similar to the number of new products with CDER priority review or with “important to major” therapeutic benefit granted by the French reimbursement authority, we expect that valuable innovation has been identified. A positive reimbursement decision was obtained in 76 cases (69%). Granting of ATV (P <.001) was the most significant factor affecting the reimbursement decision (OR and its 95% CI: 17.9 [5.5-58.3]), suggesting the Belgian reimbursement procedure also rewards value for innovative products as EPF recommends. Because more than 50% of the variance still remains unexplained, one cannot confirm or reject the impact of other factors (financial, economic, etc) possibly affecting the reimbursement decision.

The Adaptive Designs session at the Third FDA/DIA Statistics Forum presented an important step in the scientific merits and evaluation of two recently emerging drug development adaptive paradigms: exploratory versus confirmatory. After highlighting the different paradigms, several questions addressing critical issues in confirmatory clinical trials were posed and discussed by an expert panel. So far, adaptive design and analysis methods have focused mostly on individual trials. The merits of a single adaptive trial may be better suited to the context of a drug development program. We articulate the roles of modeling and simulation for modem protocol design via clinical scenario planning in a phase 3 development program. The clinical scenarios consist of a combination of effect sizes, variability, placebo response, and type I and type II errors. The models are mainly used to improve the precision of effect estimate. These topics are further discussed in Part II.

In this article we investigate success probabilities and effect estimates for several standard phase 3 programs consisting of two pivotal studies, each with placebo and either one or two doses. We investigate the probability of success for the entire phase 3 program as well as the resulting bias and mean square error of the effect estimates. We also investigate an alternative development strategy, where the first of the two pivotal trials uses an adaptive trial design with treatment selection at interim. The dose selection at the interim analysis of that adaptive trial triggers a second confirmatory, nonadaptive trial comparing the selected dose(s) with placebo and otherwise following the same protocol as the adaptive trial. After describing key considerations, we report the main results of extensive simulation studies.

In randomized clinical trials of antiepileptic drugs (AEDs), the seizure frequency per x days during baseline and treatment phase periods are recorded to evaluate efficacy of a drug. The seizure frequency data are often nonnormal, and hence an appropriate mathematical transformation is necessary for a statistical analysis. The most commonly used transformations in AED development research are (a) log-transformation of the seizure frequency data, and (b) calculation of percentage change (PC) from baseline in seizure frequency. The log-transformed postbaseline seizure frequency data are analyzed using a parametric ANCOVA model including the log-transformed baseline data as a covariate and treatment group as a factor in the model. The PC data are analyzed using either a Wilcoxon rank-sum test on the PCs, or ANOVA/ANCOVA analysis on the ranks of PCs including treatment groups as a factor and any covariate of interest in the model. A limited number of research works is available in the literature regarding a choice of log-transformed or PC of seizure frequency data in the statistical analyses. In this research, an attempt is made to evaluate the impacts of choosing either of the two transformations on seizure frequency data of AED trials.