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A common biotech business model is to have a lean and fast virtual organization. These organizations are established with experienced professionals who have a wide breadth of entrepreneurial experience and experience within the pharmaceutical, biotechnology or even medical device sectors. These organizations also have innovative products that are to be developed to the next inflection point, which is usually a step to reduce further developmental risk. The product can then be moved on toward regulatory development or licensed to a larger organization. Conducting early phase I or II (or a combination of both) clinical trials for the innovative product is often the mandate of these types of virtual companies. With limited human resources the organization must outsource many of the tactical and operational activities. For a clinical trial this will include the activities associated with manufacturing, distribution, regulatory, clinical operations, and safety evaluations.
The following is a case study of some of the key processes that a virtual biotech company located in the United States undertook to conduct a Phase II study in Europe.
The company was a small four-person company that had acquired the license to a small molecule that had already been in a proof-of-concept, open label trial (with good results) at a University clinical setting in Europe. The active pharmaceutical ingredient (API) in the product was well known to be safe under its current use. For this study, the API was reformulated and had a changed delivery system (nasal) and was to be used in a new medical indication: migraine prophylaxis. There was good justification for the mechanism of action applicable to migraine prophylaxis. The principle physiology of migraine onset that might be affected by this API had been originally proposed in European universities. Investigative site costs tend to be lower per subject in Europe than in the United States; subjects in studies in Europe are not accustomed to high payments per subject and they frequently conduct studies with reimbursement received for time and travel costs only. Due to this background and to the availability of key opinion leaders and active migraine clinics with a high load of potential patients for clinical studies, the biotech organization had decided that an initial tactic would be to conduct a larger Randomized Control Trial for this product in the EU.
The company wanted to assure that the clinical trial they conducted would qualify, if successful, to be a Phase II study that would be acceptable to regulatory agents in both the US and EU, as well as larger pharmaceutical companies, and be predictive of efficacy and safety parameters that would be necessary to be measured in a Phase III study. It was at this point that the company contacted Key Opinion Leaders (KOL) in the US and EU that had an understanding of the migraine trials and would help in the design and implementation of the protocol. A key finding from the discussion with the KOL is that Germany would not accept the nasal formulation due to a ban on preservatives in this type of formulation. The key components of the protocol were decided and the trial preparation was to continue.
The next key set of decisions was the selection of the vendors for manufacturing and the clinical operations.
It was decided that in order to more easily comply with the GMP provisions in the CTD, the manufacture of the nasal product should be done in Canada under specifications applicable to both US and EU regulations and standards. The advantage of selecting Canada was that Canada has a Mutual Recognition Agreement with the European Economic Area: the European Free Trade Association (EEA EFTA). Thus the manufacturer was able to assure arrangements for Qualified Person certification of the investigational medicinal products (IMPs) that they used, and the specific manufacturing process utilized GMP standards at least equivalent to those in the EU. The Clinical Trial Application form asks for details of the manufacturing specifications and assays. Sponsors must therefore ensure that they have organized the QP certification procedures and the QP has carried out any GMP audits before submitting the CTA application.
In order to comply with Clinical Trial Directive (2001/20/EC), the organization needed to ensure during the set-up process that all investigators, Clinical Research Organizations (CRO), analytical labs, etc. have the staff and facilities to comply with the Directive's requirements and be able to provide evidence that they carried out these checks. It was thus decided that the CRO was to have an office in the EU so they could manage some of the sponsor's responsibilities. The organization must be represented inside the EEA due to enforcement regulations in the CTD. Non-EEA companies can do this by delegating to an EEA-based CRO, or by setting up their own subsidiary within the EEA. The analytical lab and the clinical product distributors were also located in the EU to help comply with regulations that would reduce shipping costs and ease some communication channels with the investigators. Regional clinical research associates (CRAs) located in each of the countries were selected since they had the best knowledge of the local regulations, competent authorities (CA) and local and central ethics committees. The CRAs were also utilized to confirm translations of critical documents, such as informed consents and patient brochures. At this point, countries were selected for the study and the protocol and associated documents, like the informed consent, were generated. The existing Investigator's Brochure was updated with prior studies and recent toxicology non-clinical studies.
An optional step at this point would be to apply for scientific advice from the various sources in the EU. This would be an important step for studies that include pediatrics, orphan indications, cancer studies or studies with novel endpoints or biomarkers. For this case study, it was determined unnecessary at this time.
The next step was to initiate the application process. The first step in this process is to receive a unique protocol number from the European Union Drug Regulatory Authorities using the EudraCT or Community Clinical Trial System registry program (EudraCT). Because the application is relatively simple, the organization completed the forms themselves and obtained the registration code for the subsequent applications to the CA and EC.
Once the EudraCT number is received, the next, perhaps surprising, step is to initiate insurance applications. Clinical Trial insurance is required under the CTD but each country has unique individual requirements. For example, The Netherlands has the following requirements:
Expect that the insurance company will actually review the protocol, IB and the Informed Consent and may come back with comments. The brokers will want to know the individual investigators for the study as well. This process can take as long as two months but can occur in a parallel manner with other pre-study activities.
The CTD application forms are quite specific and require substantial proof of compliance with the different components:
The EudraCT web pages have an extensive Section J that summarizes the different sections of the completed applications and what sections are needed for the CA and the EC in each country. The Module 1 is where you add any prior scientific advice from any of the groups in the EU, such as the pediatric or orphan indication groups. This section also includes the letter enabling a CRO to act on behalf of the sponsor. Modules 2 and 3 are subject- and protocol-related where some sections go to the EC, others go to CA and still others are sent to both groups. Module 4 includes the IB and IMPD information; be prepared to summarize all active trials with this IMP. This section is also where you have the declaration of the QP for complying with the manufacturing process to GMP specifications requires under the CTD. Module 5 is facilities- and staff- related and thus includes the manufacturing facility and the CVs of the investigators and medical monitoring, as well as information about support staff in each site. Module 6 includes the required finance- and contract- related materials. This includes the insurance requirements, compensation for subjects and investigators as well as the contract between the sponsor and clinical sites.
If the information is complete, most countries will be able to give approval at the CA within 60 days. The applications at the EC in the different countries for this case study were more problematic. There were both central EC and local hospital-based EC that had to be submitted and then the time for review was affected by summer schedules. Bottom line, it took more than eight months from the date of EudraCT application to get every site enrolling.
In the course of this case study, we discovered:
Subsequent to this study, some of these submissions issues have been resolved so that some parts of the applications in the UK can take place via a centralized FTP secure server.
The operational aspects of the trial went relatively smoothly. The biotech managers insisted on having at least monthly teleconferences with all the key vendors in attendance. This worked relatively well except for the issue with drug shipments and resupply. The study was not ideal for the clinical supply vendor and the automated clinical trial service did not work well in EU because of several issues in email/fax log of enrollment and drug supply. There were also computer and power glitches that resulted in delays in drug release and timing of shipments. The electronic logging system was often problematic and needed periodic manual checks. The solution was that the different vendors and regional CRAs provide extra communication to sites as necessary.
Managing any clinical program is complex but managing a clinical trial with a virtual team from the US created some problems. However, most were solvable. The EU (as any clinical trial) has strict regulations but the CTD has added a dimension due to differences in each Member state in the EAA. The use of different vendors helped the company get the best advice but did require a lot of forethought on communication and relationships between the different vendors. Internal management of this project would not be possible without a strong project manager from the primary CRO in excellent communication with the sponsor.
Dr. John McLane has over 20 years of progressive experience in all phases of global development with both large and small pharmaceutical companies. His knowledge basis has led full development projects with over 50 clinical programs and to successful INDs, NDAs, IDEs and EMEA/CTA applications. Key strengths include the early development of clinical and regulatory strategies, and negotiating with regulatory officials. Dr. McLane has developed and implemented complete medical regulatory, clinical, and marketing strategies and programs in these therapeutic areas. Additional development activities include developing business rationale, teams, programs, and strategies for early clinical candidates in metabolic diseases, respiratory and oncology areas. He has also successfully completed in- and out-licensing reviews and negotiations including those for orphan indications. He possesses particular expertise in the initial formation and development of new start-ups and early clinical companies and has provided major contributions to business plans and presentations to venture capitalists for significant fund-raising.
Prior positions included VP Pharmaceutical Development (Ariston Pharmaceuticals, Inc.);VP of Clinical and Regulatory Affairs (Milkhaus Laboratory, Inc.); Co-Founder (Catalyst Oncology); Director of Early Strategic Planning (Hoffman-La-Roche); and Director of Medical Science and Safety Teams (Roche Laboratories). Contact Dr. McLane at firstname.lastname@example.org.
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