Statement of Dr. Carl Peck
U.S. Department of Health and Human Services
Secretary’s Task Force on Drug Importation
“stakeholder meeting discussion that will focus on the international
and academic perspectives on issues related to importation”
Rockville, Maryland, April 27, 2004
Thank you for the privilege of presenting my views on aspects of the safety and effectiveness of imported drugs. I am Carl Peck, M.D., Ph.D. (h.c. Uppsala), Professor of Pharmacology and Director of the Center for Drug Development Science (CDDS) at the Georgetown University, and Chairman of NDA Partners, LLC, an international consultancy to investors and mid-stage biotechnology companies. I am trained in medicine and clinical pharmacology, and have more than 30 years experience in research and testing of human drugs, including six years as Director of FDA’s Center for Drug Evaluation and Research (CDER, 1987-1993) and ten post-FDA years as a researcher, teacher, and consultant to the pharmaceutical and biotechnology industries.
I would like to offer my experience and understanding of drug quality, safety and effectiveness as a resource to the Secretary’s Task Force on Drug Importation. While many questions have been raised for and by the Task Force, I think I can best serve by first explaining FDA standards for drugs approved and distributed in the USA, followed by offering some points to consider concerning challenges and implications of assuring quality, safety and effectiveness of imported drug and biological products. I shall not specifically cover controlled substance drugs.
Why do we have confidence in FDA approved drug products? It is useful to distinguish between the active (therapeutic chemical(s) or biological substance(s)) and inactive ingredients (non-therapeutic chemicals) in a company’s drug product, from the drug product itself. The latter comprises a particular embodiment of the active and inactive ingredients, called the drug formulation (e.g. tablet, capsule), and is a specific creation of the manufacturer. Very often, the formulation itself and it manufacture have important influences on the safety and effectiveness of the drug product. In the USA, by force of law, manufacturers of prescription, non-prescription drugs and biological products must meet scientific standards of quality and performance that assure safety and effectiveness as claimed in all communicated information that is distributed by the manufacturer in conjunction with the product. These standards are met by submitting evidence of compliance with these standards to FDA, which is carefully reviewed by FDA scientists. In addition, FDA conducts field inspections and audits of manufacturing facilities and undertakes periodic manufacturing re-inspections and analyses of sampled products in the supply chain.
FDA drug chemical quality standards pertain to accurate information as to the identity and amount (or dose) and source of the principle active ingredient(s), inactive ingredients, and impurities in each product. To meet FDA requirements and agreed specifications, manufacturers must undertake extensive chemical analyses of the active and inactive ingredients in the drug product (using modern analytical methods such as chromatography, and mass spectrometry), along with analytical procedures for monitoring and assuring consistency of the ingredients during routine manufacturing, distribution and storage.
Further, drug formulation quality, is assured by similar scientific standards applied to the company’s selection and manufacture of its particular formulation of the drug – e.g. oral tablet, capsule or liquid, intravenous, intramuscular or subcutaneous liquid medium forms, etc. Requirements typically include laboratory testing for tablet or capsule size, hardness, and dissolution profiles in simulated gastric juice, strict specifications and control of all aspects of product manufacture , distribution, and conditions of storage, and a special human clinical trial to confirm so-called bioequivalence. Storage condition testing involves many months of evaluation of various chemical and formulation quality investigations under several conditions of expected and extremes of temperature, humidity, storage duration, and transportation conditions, to assure lack of degradation, formation of unsafe impurities, etc.
Human bioequivalence testing involves confirmation of near identical profiles of drug active ingredient concentrations in the blood of humans sampled various times following ingestion (or injection) of a referenced drug product (used in previous clinical trials or approved for marketing) and the test product intended for marketing, generic copy, etc. The bioequivalence test, according to FDA clinical and statistical standard procedures, provides the basis for expecting that non-identically formulated or manufacture products are clinically comparable in safety and effectiveness. Although bioequivalence tests are best known for their use in generic drug testing, most approved new drug products have themselves undergone numerous bioequivalence tests during pre-market development, and may undergo additional bioequivalence tests when significant changes in manufacturing, formulation, or even source of active ingredients are made after marketing. Typical bioequivalence trials employ 16-24 normal male subjects, each studied for a day or more on two different occasions, a week or more apart, once with each drug formulation – at a cost of $125 – $300K.
Safety and Effectiveness of a new drug to benefit patients suffering from a particular disease are proven via extensive animal and human clinical trials that employ drug products characterized and controlled by the above listed quality and performance standards. It is assumed that once safety and effectiveness of a new drug product are adequately proven, the continued safety and effectiveness is assured by closely adhering to the above listed strict CMC, formulation, manufacturing and bioequivalence quality standards. A more detailed list and explanation of these procedures employed within the U.S. pharmaceutical and regulatory system can be found in a recent letter from FDA to Mr. Rick Potter, New Hampshire Pharmacists Association (FDA Docket 2004N-0115).
As a result of compliance with requirements for consistency and quality of active ingredient and documented CMC testing, and consistent adherence to every detail of manufacturing, storage, and distribution specifications and storage conditions, Americans have long enjoyed approved drugs obtained at their hospitals, pharmacies, drug stores and doctor’s offices that are reliably safe and effective.
Points to consider with respect to safety and effectiveness of imported drug products. Drug products that are apparently identical to FDA approved drug products are under consideration for authorization for expanded importation into the U.S. It is useful to consider two broad categories of such drugs, distinguished by their origin, manufacturing, quality testing, transportation, storage records: Category I - FDA approved products that are manufactured in the USA or approved foreign facility(s) (full compliance records are available), that reenter (or enter) the USA as an import, and Category II - drug products, not approved by FDA, that first enter the USA from foreign manufacturing sites, without records of quality and performance testing, regulation by competent regulatory authorities, transportation or storage conditions.
1. Category I and II drugs differ significantly in the potentially available information about quality and performance of the products, and therefore vary in the burden and cost of assuring product safety and effectiveness. Apart from verification of regulatory and manufacturing pedigree and non-counterfeit status, reentry of Category I drugs would raise mainly questions of performance deviations due to effects of extreme transportation and storage condition effects on drug product performance in patients. Such concerns could be met by employment of procedures for full documentation of the sojourn history (including storage conditions), random testing, or, triggered by extreme sojourn histories, be required to meet dissolution specifications and even limited bioequivalence tests.
2. Category II drugs present the greatest challenge for assurance of safety and effectiveness. Confidence equal to that enjoyed by Americans with domestically manufactured and distributed FDA approved drugs would be possible by requiring foreign source marketing organizations to meet all CMC, formulation, and bioequivalence standards required of domestic products, either directly through FDA (e.g. file a new drug application), or indirectly via agreement with competent foreign regulatory authorities to enforce FDA standards. In any case, implementation of such an expansion of FDA involvement or collaboration with foreign regulatory authorities would be a daunting, massive, complex and expensive proposition.
3. There are two implications of relaxing importation restrictions that are worth considering. The first concerns an unintended, potential increase in counterfeit drugs. Permitting Category I drugs to be imported freely may quickly result in a huge sellers market across US borders, strongly luring counterfeiters to join in the bonanza market created. Compliance efforts to counter this threat would be costly and imperfect, leading to entry of unsafe or ineffective products. The second concern relates to the effect on FDA resources with respect to the manpower drain, if tasked to provide increased enforcement activities. A full financial forecast is advised, along with consideration of collecting user fees from foreign distributors and manufacturers who become part of the drug importation process to support the increased FDA resource requirements.
