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April 15, 2009 (Vol. 29, No. 8)

Spotlight on the FDA

Outsourcing Clinicals; Medical Journal Articles; and Contract Manufacturing Liability Issues

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    Bruce F. Mackler, Ph.D., J.D.

    In today’s financing environment, the absence of early clinical data presents a high barrier to obtaining funding. Investors often say “show me the clinical data that show that the drug is safe and works and I will show you my money.”

    As a result, biopharma companies have moved into early non-U.S. clinical trials that have lower safety data burdens. These studies are being conducted in less wealthy (a.k.a., developing) countries, where Phase I trials can be more rapid and less costly. This strategy has been promoted by CROs established in these countries.

    Non-U.S. studies must be reported to FDA when an investigational product starts the IND process. Companies usually emphasize the first-in-man safety aspects to FDA and tout the proof of concept to venture capitalists. The strategy is to use such data to move into Phase II.

    FDA is growing increasingly skeptical of the quality and adequacy of the local governmental oversight of these studies; thus, the regulatory value of these non-U.S. studies with FDA may be diminishing, particularly for Phase III studies. 

    FDA reportedly is beginning to educate and train governmental regulators in other countries to better analyze protocol design and monitor clinical trials. Biopharma companies seeking to start such studies will be faced with new challenges and higher local regulatory requirements.

    For instance, drug companies are asking if they can test their new drugs in India before they are demonstrated to be safe in the company’s home country. Patient advocates argue that individuals often enter trials because they have no medical insurance and no other option to receive advanced medical care. Although this concern is increasingly expressed in developing countries, these nations are reluctant to cut off the clinical trial dollars and medical access.

    Biopharma firms planning early non-U.S. clinical trials need to anticipate the evolving FDA concerns, and act to increase the acceptability of such studies by improving the quality control of these trials and the adequacy of informed consent disclosure of study risks. These companies should also advance the local standards of medical care to make the data more relevant to U.S. standards.

    In planning non-U.S. studies, companies need to be aware that cost and regulatory burdens will be increasing and trials may be slower than anticipated. But, compared to getting a first-in-man new drug into a Phase I through FDA in the current regulatory environment, it may still be faster to go offshore to generate early data. 

    A regulatory constraint frequently overlooked by early-stage companies when planning to go offshore is the investigational new drug export restrictions, which mandate that companies will need to manufacture their Phase I drug under cGMP offshore, which is an added expense and also involves the transfer of technical know-how.

    EMEA concerns about the acceptance of clinical data from trials conducted in developing world countries, particularly pivotal study data, expressed in their EMEA strategy paper (December 5, 2008) parallel the concerns expressed by FDA.  Approximately one-third of the patients in pivotal studies submitted in MMAs were recruited in developing countries. EMEA will seek better verification through inspections of the GCP and informed consent compliance of these studies.

    Companies contemplating foreign (non-EMEA and U.S.) clinical studies would wise to increase the level of monitoring and auditing oversights for such studies during Phase II to verify compliance before starting Phase III pivotal studies at such sites. One strategy is the potential sharing of independent audit reports to demonstrate adequate GCP and informed consent compliance with regulatory authorities when after submitting MMAs/NDAs. Also, based on public statements by Indian clinical study experts, companies may have to bring GCP and ethical standards up to western levels through training at clinical sites, which is another hidden expense in assessing the cost effectiveness of such trials.

    Given some ethical concerns about U.S. for-profit institutional review boards (IRBs), look for the FDA to also increase domestic inspections of IRBs after the recent General Accounting Office (GAO) report.  The GAO ran a sting operation and submitted sham trial protocols to a for-profit IRB requested by several congressmen, which exposed a 99.97% approval rate, with the approvals being unanimous.  Patient groups have recently voiced concern about the weakness of the IRB system and FDA’s oversight, a perception that results in less U.S. patients interested in U.S. clinical trials. Another major concern is the lack of transparency in terms of which IRB has oversight responsibility of a given clinical trial. Do not be surprised if Congress tries to address this in the future.

    It is likely that the cost and investment of both domestic and nonwestern clinical studies will grow particularly for Phase II and III studies, but the flexibilities for early first-in-man Phase I studies will still be attractive in developing countries. This will remain a critical opportunity for start-up and early-stage biopharma companies to get early clinical data, now a prerequisite for VC funding.

Posted 5/4/2009 by QA Manager

As a Quality professional in biotech working with a contractor who appears to be overly concerned with their liability, I think the FDA needs to seriously spell out their expectations in a written guidance. Has this been done? I personally do not understand as an IND or NDA holder, where a contractor can be held responsible for how I intend to or ultimatley do use the products I ask them to make for me.


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