Drug Development and Approval: Can Faster be Better?
By Dr. David G. Barnes

There is no question that the era of the blockbuster drug is drawing to a close. We are told that small molecule pipelines are drying up and that biotechnology will come to the rescue. In fact, the burgeoning growth of biotechnology is roundly touted as the saviour of our sick patients, our sick relatives and our (some may say sick) economy. It has even been said that biotechnology will usurp the computer age as the primary determinant of the direction, and quality, our lives will take in this century. Of course, the linchpin in all of this promise is the regulatory approval of the products.
It is more difficult than ever before to obtain approval to market a biological therapeutic, or any other drug for that matter. The development life cycle of therapeutics is growing steadily longer and the expense has escalated. Everyone has seen the mind-boggling numbers: $800 million US and up to 10 years to develop and register a new drug (if it’s approved, that is). Canadian Business magazine reported in 2002 that “In Canada, getting regulatory approval can cost more than developing a genetically modified product in the first place.” (Sept. 2, 2002, pp. 28-35)
As drug regulatory policy continues to develop — and make no mistake, regulations grow and tighten even in the absence of headway toward reducing submission review times — the pre-market burden on innovators increases. This translates to high attrition rates amongst young R&D companies. Promising ideas are left unrealized, the economy is denied growth, and ultimately the patient is denied new treatments. The risks and costs of drug development beg the question: why bother?
Like never before, we are dissecting the molecular pathophysiology of disease. Biotechnology is allowing increasingly targeted interventions. Demographics, social expectations and disease burden on patients, families and the economy combine to define a massive market for safe and effective therapies. While the travails of drug development are heavier than ever, the market potential for biologics (e.g., cells, blood products, recombinant therapies, vaccines, etc.) and for biotechnology-derived drugs (e.g., peptides, peptide vaccines, etc.) — not to mention the potential for benefit to humanity — is infinite. But, if the development of biotherapeutics and biotechnology-derived drugs is to come anywhere close to its potential, concerted efforts by regulators and industry toward improving risk-management will be required in order to improve drug-approval processes and optimize safety assurance.
Lobbying by industry and patient groups has led to the general recognition that the drug-approval process must change, and that the changes must be more substantive than simply addressing New Drug Submission backlogs. What is required is faster access to new drugs, and faster and less onerous approval processes. These goals are achievable, but the approach must be heavily collaborative.
Contrary to popular myth, regulators are not evil incarnate; their raison d’être is not to reject drug submissions. (Illness is a great equalizer — everyone wants a cure for cancer.) Regulators do, however, suffer from significant resource constraints. Like other government activities, drug regulation must fight for every piece of the budgetary pie. An excellent example of the need for co-operation between regulators and industry is the case of novel therapeutics for which there is no regulatory precedent. Careful drug-development planning and a collaborative approach can mitigate against the risk of stalling drug-development projects. However, fiscal reality dictates that at least for the foreseeable future, industry must be a major driver in ‘evolving’ regulatory processes.
In order to succeed, industry and government initiatives directed toward improving drug approval must focus first on safety. Leading pharmaceutical companies have recognized this and continue to devise and implement risk-management strategies in product development. Industry is generally very good at collecting data and following patients using patient registries. This activity should be encouraged and increased. Innovative growth in pre-market risk assessment includes the use of mathematical modelling to predict risk or to flag products pre-market for enhanced scrutiny post-market, and the use of systematic reviews to support product safety claims (see below).
Undeniably, the yin and yang of drug approval are pre-market evaluation and post-market surveillance: it is unrealistic to believe that pre-market evaluation could be streamlined in the absence of improving post-market surveillance. There is tremendous room for improvement in this zone. Moreover, there is the capacity as well.
Currently, the cornerstone of post-market surveillance in Canada is the spontaneous reporting of adverse drug reactions (ADRs). We are woefully bad at it compared to the U.K., New Zealand, Australia and Japan. Many health-care practitioners (HCPs) aren’t versed in ADR reporting and have no incentive to report. There is no mechanism for communicating to reporters that an ADR report has been received and no mechanism for feedback to reporters or for education. In order for passive post-market surveillance to work better (i.e., increase reporting rates, numbers of HCPs engaged in reporting, quality of reports), Health Canada could collect ADR data using an easy and secure Web-based system, allowing feedback and education.
Regulators don’t currently have the capacity to do cohort analyses (this could be addressed using linkable databases containing ADR and drug-utilization data), nor do they have access to good denominator data. Industry, however, is ideally situated to follow cohorts and collect drug-utilization data, and should be encouraged to increase activity in this area. Meanwhile, pre-market regulatory approval must take into account the safety assurance coming out of any such industry initiatives. But don’t expect that government will bear the financial cost of enhanced post-market surveillance alone, particularly if there will be any perceived benefit to industry.
Some degree of increased harmonization of drug review needs to be explored as an option. There is no unassailable reason why regulatory jurisdictions couldn’t share some aspects of the evaluation of standard submissions or parts thereof, particularly if a sovereign jurisdiction maintained the right and capacity to conduct the evaluations internally. For jurisdictions with smaller populations or limited resources, this could make big sense.
Regulatory policy should constantly evolve to optimize the scope of what constitutes ‘reviewable’ evidence. The new Natural Health Products Directorate (Ottawa, ON) has developed a comprehensive roster of clinical evidence it will accept for review in support of a natural health product. Ranked highly as favoured evidence (first, in fact) is the systematic review. A systematic review consists of the comprehensive identification and evaluation of published and unpublished (‘grey’) literature. It is designed to answer a research question(s) developed a priori. The review is conducted using a rigorous, standardized methodology, and, once combined, data may be subjected to statistical analysis (meta-analysis) — again, according to strict criteria. There is ample room for developing the use of the systematic review as a tool for generating supporting evidence for drug approval.
Clinical trials continue to be inefficient and occasionally unsafe. Pain points include the following:
·     competition for some patients, such as those with cancer;
·     steadily shrinking pools of qualified investigators;
·     investigational sites and investigators that are not comfortable — or even compliant with — good clinical practice guidelines (ICH GCP);
·     slow and/or erratic ethics board approval;
·     turn-of-the-century systems (to use the word loosely) for data capture, management and quality assurance.
Canada has many well-developed disease and patient networks. Still, some argue that all patients entering a tertiary care centre in this country should at least be offered screening for a clinical study (easily justified on the basis that patients enrolled in clinical trials receive better care). This is not anywhere near being the case.
Centralized ethics review, or specialized ethics review boards (akin to centres of excellence) might be an option for improving the ethics approval process. Standardized training for board members and standardization of operating procedures for ethics review boards should also be considered.
Patient enrolment in clinical trials should balance unnecessary patient exposure to investigational drugs against statistical significance in hypothesis testing. Data accrued from every single patient should be meaningful and ‘evaluable.’ Clinical trial patients (more specifically, the data on those patients) are regularly found to be unusable because of poor quality, including inconsistent or incomplete data. The cost in dollars and statistical power of these ‘lost patients’ is significant. Taking into account the logistical headaches and data-quality issues, it is remarkable that some studies get completed at all.
According to the Tufts Center for the Study of Drug Development’s Outlook 2003, “Firms will expand their use of e-technologies to reduce the length and cost of clinical development by improving the investigator site selection process, reducing delays in recruiting patients for clinical trials, lowering trial monitoring costs, and permitting quicker, cheaper collection of clinical trial data.” (TCSDD Outlook 2003, p. 2; http://csdd.tufts.edu/InfoServices/OutlookPDFs/Outlook2003.pdf).
It is safe to say that reliable electronic data capture and management will one day be the norm; until then, the collection and collation of paper-based data will be an expensive bottleneck in clinical trials. There has never been a better time nor place for widespread development and adoption of electronic data capture and management in clinical research.
Canada is well positioned to benefit from innovation and development in medical biotechnology. It is still regarded as an excellent place to conduct clinical research. But there’s room to improve and room to lead.
Dr. David G. Barnes is managing partner of BioTheraGene Clinical Research Corp. (Ottawa, ON), chief executive officer of Boreal Primum Inc. (Montreal, QC), and regulatory advisor to and member of the board of directors of TrialStat Corp. (Ottawa, ON). Barnes is director of Clinical Drug Development, Chalmers Research Group, Children’s Hospital of Eastern Ontario Research Institute (Ottawa, ON) and investigator, University of Ottawa Evidence-based Practice Center (Ottawa, ON). Barnes is a physician, molecular biologist and consultant to industry and government in the clinical development, regulation and safety of biologics. He is a former clinical evaluator, Biologics and Genetic Therapies Directorate, Health Canada.