Is Ignorance Of Regulations Delaying Your New Product Launch?

By Alex Kanarek, Ph.D. and Patricia Seymour

Sometimes drug development can feel like a Sisyphean challenge in the progress from laboratory bench to the clinic and, for a small percentage of companies, to the market. Global regulatory requirements, embodied in regulations governing good laboratory practice (GLP), good clinical practice (GCP), and good manufacturing practice (GMP), collectively referred to as GxP, can intensify this frustration. These requirements exist, however, for very valid reasons and when followed properly can actually decrease the risk and frustration that frequently go hand in hand with drug development by providing a clear compliance roadmap.

The FDA is toughening its approach
Recent moves by the FDA have made compliance with GxP even more critical. Deborah Autor, director of CDER’s (Center for Drug Evaluation and Research) Office of Compliance, warned participants at a September 2009 conference that “sloppy” new drug applications (NDAs) or GMPs may be considered red flags by the FDA, prompting regulators to take a closer look at other company processes. She added that the FDA’s new enforcement initiative will boost the number of warning letters, product seizures, injunctions, and clinical investigator disqualifications. The speed of enforcement actions also is likely to increase. The agency requires a company’s response to a Form 483, issued on completion of a facility inspection, to be made within 15 working days of its receipt. Delays will no longer be tolerated. At the next stage of regulatory activity, a warning letter must also be answered adequately within 15 working days.

It is therefore essential that all staff involved in the drug development process are fully up-to-date on current regulations and are complying with them. This can be accomplished through routine and thorough training and monitoring of staff that perform GxP activities. Both the training and the monitoring should be properly documented. The warning letters issued by the FDA are full of instances of noncompliance with GxPs that were due either to ignorance of the actual regulatory requirements, or plain disregard for the requirements, which is a more serious issue. In either case, the key result will be a delay in obtaining approval to begin clinical trials or a delay in receiving market authorization for the product.

Typical Noncompliance Problems
Noncompliance is typically broken down into a few major categories, including deficiencies in quality management, inadequate documentation of procedures and processes, and failure to investigate deviations from GxP. Recently issued warning letters can be found at the FDA website (http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm). Several representative examples are provided here to give an overview of the FDA’s current focus.

GLP noncompliance causes delay in the approval of an IND (investigational new drug).
A key part of the IND documentation is the report on the toxicity of the drug in laboratory animals. These studies must be performed in compliance with GLP. The FDA has cited numerous companies for failure to follow the basic GLP requirements.

• “Failure of the study director to ensure that all applicable good laboratory practice regulations are followed.” Although the quality assurance unit (QAU) monitors the study, the study director is personally responsible for the compliance of the study with GLP.
•  “Failure of the testing facility management to establish a QAU responsible for monitoring each study.” The QAU maintains the master testing schedule and the test protocols and monitors each phase of the study. Without evidence that these activities have been performed, the FDA will not accept the toxicity data.
•  “Failure to conduct nonclinical laboratory studies in compliance with the protocol.” This is an extremely common fault. There is no point in creating a study protocol if it is not going to be followed.
• “Failure to ensure that each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study has the education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions.” This highlights the importance of having properly trained individuals conducting and/or supervising the studies.

These quotes are taken directly from letters addressed to specialist testing laboratories, but the same noncompliance issues have been found within companies’ own testing facilities. They indicate an ignorance of the regulatory requirements or, even worse, a conscious decision to disregard compliance. In each case, the net result was, in the agency’s words, “Your violation of the FDA regulations outlined above resulted in the submission of unreliable data to the sponsor.” If the data is unreliable, the IND will not be approved.

GCP noncompliance causes costly delays in NDA/BLA (biologic license application) approval.
The conduct of clinical studies must comply with the GCP regulations. The regulatory authorities will disqualify clinical investigators from participating in further studies if they persistently demonstrate ignorance or intentional noncompliance with GCP requirements. Clinical noncompliance examples include:

• Failure to follow the clinical protocol and any conditions imposed by the Institution Review Board (IRB)
•  Failure to ensure adequate application of the informed consent procedures to protect the subjects
•  Lack of personal conduct or supervision of the study by the principal investigator: This has been a concern of the FDA for some time, and the agency issued a new final guidance in October 2009 detailing the conditions under which it is acceptable to delegate tasks within a clinical trial and the required qualifications for staff to whom tasks are delegated. This especially applies to multisite trials, where a qualified investigator must supervise each site.
• Failure to maintain adequate and accurate case histories
• Failure by the sponsor’s QAU to monitor the study adequately
•  Failure to report unexpected clinical reactions to the IRB and the sponsor
• Failure by the IRB to follow written procedures in its operations and to monitor adequately the studies for which it is responsible

The sponsor carries final responsibility for all compliance issues. There must be a written agreement between sponsor and investigator which specifies the duties and responsibilities of both parties. The sponsor’s monitors must be sufficiently trained and educated to be able to discover and correct instances of noncompliance while the trial is in progress. Between Jan. 1, 2009 and Oct. 15, 2009, 17 clinical investigators received warning letters from the FDA. In all of these cases, the final approval of the product was delayed while the problems with the clinical studies were resolved.

NDA documentation problems and GMP noncompliance issues
The format of an NDA is now defined by the Common Technical Document, created by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The actual content of the application is defined in the regulation 21CFR314, “Applications for FDA Approval to Market a New Drug.” A clear understanding of the requirements of both these documents is essential to avoid delays in approval of an NDA.

As drug development progresses through the clinical stages, the GMP requirements increase. The batch documentation and testing records are included in the NDA, so any instances where activities deviated from the approved operating procedures or drug specifications must be investigated and documented to be in compliance with GMP.

Typical GMP noncompliance issues in NDA documentation include:

• Inadequate control of raw materials
• Inadequate data on manufacturing process development
•  For biopharmaceuticals, inadequate data on cell line development and testing
• Absence of validation data for manufacturing processes and analytical methods
• Incomplete batch production/testing records
• Lack of adequate justification for drug specifications

Further instances of GMP noncompliance may be discovered by FDA inspectors during the preapproval inspection of the sponsor’s manufacturing and testing facility(ies) or that of a contract manufacturer. These often include citations of the quality unit for:

•  Failure to investigate out-of-specification results or SOP deviations
• Inadequate corrective and preventive action (CAPA) plans
• Lack of regular GMP training for all personnel involved in manufacture and testing
• Poor documentation control

In summary, there are many examples where a company can suffer delays in the launch of a new product and incur additional work and expenses by virtue of not devoting sufficient attention to training and monitoring of key personnel on the relevant national and international GxP regulations to ensure compliance. In smaller companies, trade-offs are unfortunately made in favor of more research and development personnel and fewer in quality assurance and regulatory affairs, often to their later regret. In such cases, the FDA specifically advises companies that, if they do not have the expertise in-house, they should employ consultants to ensure that compliance is complete.

About The Authors
Alex Kanarek, Ph.D., is a senior consultant at BioProcess Technology Consultants, Inc. The group specializes in strategic, technical, and regulatory consulting services to the biopharm industry. Dr. Kanarek has more than 30 years of experience in the biopharm industry with the Wellcome Foundation (now GSK) and Connaught Laboratories (now Sanofi Pasteur).

Patricia Seymour, MBA, is a senior consultant at BioProcess Technology Consultants and has over 20 years of experience in the biopharm industry. Her expertise spans the development and commercialization spectrum, including biologics and small-molecule development and manufacturing, supply chain strategy and management, and operations leadership.