Historia de la Biofarmacia

1. Primeros aspectos regulatorios

Texto tomado de Skelly JP. A history of biopharmaceutics in the Food and Drug Administration 1968-1993. AAPS J. 2010 Mar;12(1):44-50. doi: 10.1208/s12248-009-9154-8. Epub 2009 Nov 20. PMID: 19936940; PMCID: PMC2811644.

"The sulfonamides were introduced in the 1930s as the first truly effective treatment for infectious disease. Because they were insoluble in aqueous fluids, parents had to crush the tablets before dosing their young children. One company solved this problem by introducing a soluble dosage form, an “elixir of sulfanilamide.” Prior to 1938, one could introduce a drug product without any toxicity testing or demonstration of effectiveness. While the elixir of sulfanilamide (solubilized by ethylene glycol, a component of antifreeze) facilitated the dosing of children, it poisoned them. When I joined FDA, I reviewed the files containing letters written to President Roosevelt by grieving parents, who upon their doctor’s orders unwittingly slowly poisoned their own children. The angst expressed in those letters was very moving. Following the deaths of those 107 children in September and October of 1937 (1), the government in 1938 enacted amendments to the Food, Drug and Cosmetic Act of 1906 requiring toxicity testing prior to the introduction of any medicinal into the marketplace.

The Food and Drug Administration (FDA) medical officer’s reviews of the first few New Drug Applications to be filed under the provisions of the new law were on the order of “The drug was administered to 12 rats: (6 male/6 female). After three days no toxicity was observed. Looks OK to me! JPS”. Both the application and medical officer’s review took up less than a single page. As time passed, the toxicology requirements became considerably more stringent. By 1962, the requirements included chronic as well as acute toxicity testing. Also testing in several species was required. Nevertheless, efficacy data were neither required nor submitted until the October 10, 1962 amendment required it.

Thomas Rice, an FDA Inspector in Cincinnati, notified FDA headquarters in Washington DC of overt manipulation of an investigation of Mer-29, which was being studied as a cholesterol-lowering agent (personal communication from Sam Fine, FDA Associate Commissioner for Compliance). An inspectional task force from Washington appeared at the company the next day and verified Rice’s information. Francis Kelsey, M.D., Ph.D., already concerned with the same company’s failure to submit adequate toxicity data for Kevadon (thalidomide), a drug then being widely marketed in Europe, was part of that investigative team. Although under great pressure to approve thalidomide, she resisted. Eventually, it became evident that phocomelia was associated with the dosing of thalidomide to pregnant women. Nevertheless, Merrell had distributed over 2,000,000 tablets (2) for investigational use, which the Agency quickly removed from the market. For her effort, President Kennedy awarded Dr. Kelsey the “Presidents Distinguished Federal Civilian Service Award” (highest award given to a civil servant) (3). Senator Estes Kefauver’s (Tennessee) investigation of these events led to the October 10, 1962 FD&C Act amendment (the so-called Kefauver–Harris Amendments) requiring in addition to toxicological data evidence of efficacy to be submitted to the FDA, before a new drug could be marketed.

FDA interpreted the new law to mean that drugs marketed prior to the 1938 law were grandfathered and did not require FDA approval. However they also interpreted the new law as requiring efficacy data for drugs marketed between 1938 and 1962 (4). To sort things out they contracted the National Academy of Science (NAS) and National Research Council (NRC) to review the medical literature to determine the efficacy evidence then available. Several categories were established:

• Effective

• Probably effective

• Possibly effective

• Ineffective

Some drugs fell into more than one category, because their labeling included more than one indication. In such cases, it could be effective for one indication, but only possibly effective for another (1). Where insufficient data were available to make a determination of efficacy, time was allocated for a company to collect such data. In each case, a determination of bioavailability (to provide assurance that the dosage form then in the marketplace was indeed being absorbed into the body) was also required. More than 1,000 drugs were determined “not to be efficacious” and were removed from the market (1).

Following the 1938 amendment, both new and generic drugs were required to submit toxicity data, but given the lack of resources to review the submitted applications, FDA began to issue “Not New Drug” letters to the generic manufacturers. This meant they could market without having to submit data for FDA approval. Given the 1962 amendment and academic concern that the different formulations of all generics were not equivalent, FDA interpreted the new provisions of the act to mean that all generic drug formulations marketed between 1938 and 1962 had to file New Drug Applications (NDAs) and establish equivalency to the approved marketed brand.

While one segment of the pharmaceutical industry looked with favor on this approach, another segment viewed the FDA’s action less favorably and went to court to prevent implementation. Eventually, the courts ruled in FDA’s favor concerning the innovative section of the industry. The situation in the generic section of the industry was considerably more complicated. Congress, not anticipating the developing situation, had not enacted any legislation permitting the filing of generic drug applications. The FDA, having withdrawn the “Not New Drug” letters, established an “Abbreviated New Drug Application” (ANDA) system (1), which required FDA approval before a generic drug product could be legally marketed. Under this system, neither toxicological nor clinical studies would be required on the drug, inasmuch as FDA already had that information in the innovators’ new drug application. Essentially, the ANDA required the filing and FDA approval of Chemical Manufacturing Controls (CMC) data and a demonstration of bioequivalence to the innovative (i.e., NDA) marketed product.

This led to several problems. Some in the innovative section of the industry were incensed that FDA would use their data to approve competitive products and lobbied to force the generic industry to perform full clinical and toxicological studies. On the other hand the generic industry argued that no law existed that would require them to file any information with the agency. This latter group felt that they only had to meet United States Pharmacopeia (USP) criteria in order to market their product (5,6). The courts ruled in favor of the FDA position in regard to the use of toxicology and clinical data, but two Federal Circuit Courts (Florida and New York) ruled in favor of the position put forward by the generic drug companies. Nevertheless, Federal Marshals at the request of FDA were intercepting shipments of these generic drug products from New Jersey to Florida, inasmuch as Florida had enacted a state law permitting the marketing of these generics in Florida. This resulted in another lawsuit in New Jersey, where the Federal Circuit Court disagreed with the Florida and New York Circuits requiring, thereby, review by the US Supreme Court.

The Supreme Court ruled that although Congress had not enacted permitting legislation, it was in the interest of the American people that FDA assure the equivalency of generic drug products. FDA, which had published proposed regulations for both innovator and generic drug products in 1972 and again in 1975 (7), then published them in final form. They became effective on July 7, 1977 (8).

While the issue was being pursued through the courts, Senator Ted Kennedy (Massachusetts) became interested in the issue. Congress had some time previously established the “Office of Technology Assessment” (OTA), but had never activated it. Senator Kennedy appointed a former New England congressman to head the office and began an immediate inquiry of the USP/FDA regulatory struggle, especially whether bioavailability testing of generic products was essential or whether meeting USP criteria was sufficient. OTA convened a panel of ten senior medical consultants, including two pharmacy professors, Dr. Sidney Riegelman (Chairman of the Department of Pharmacy at UCSF) and Dr. James Doluisio (Dean, College of Pharmacy, University of Texas): The other eight members were clinicians. After a series of meetings in which the FDA and USP and others presented data, the panel (in which Senator Kennedy was very active) formulated 11 “conclusions”. Among these, four were critical (9):

• Current standards and regulatory practices do not assure bioequivalence.

• Variations in bioavailability are recognized as responsible for a few therapeutic failures.

• Present compendia standards and GMP guidelines do not insure quality and uniform bioavailability not only for different manufacturers but also among batches produced by the same manufacturer.

• Additional research to improve bioequivalence assessment is needed."

Texto tomado de Skelly JP. A history of biopharmaceutics in the Food and Drug Administration 1968-1993. AAPS J. 2010 Mar;12(1):44-50. doi: 10.1208/s12248-009-9154-8. Epub 2009 Nov 20. PMID: 19936940; PMCID: PMC2811644.

2. Bioequivalencia

"Early in 1970, serum had been collected during an FDA-contracted bioavailability study from volunteers for the purpose of determining drug bioequivalence. Five different drugs were investigated, but equivalence/inequivalence was never determined as the methodology did not then exist to analyze the blood samples. As a result many of the generic as well as innovator companies requested waiver of the required BA studies on the basis that analytical methodology did not exist so as to permit them to do the study. To address this problem, we contracted Schools of Pharmacy to conduct a review of the literature to determine whether the analytical methodology existed for performing in vivo bioequivalence studies. The results were discouraging in that the required analytical methodology was largely non-existent. We then let contracts for methodology development, mostly to academic institutions, which could then be employed for the conduct of these studies.

Additionally, a Biopharmaceutics Laboratory was established under Dr. VK Prasad, which not only developed methodology for the conduct of these studies, but conducted surveys of marketed generic dosage forms. Following procedures developed under Professor Wagner’s contract, samples of innovator and generic dosage forms (e.g., digoxin 0.25 and 0.5 mg) were picked up by FDA Field Inspectors and analyzed by Dr. Prasad’s laboratory and FDA’s National Center for Drug Analysis (NCDA) in St. Louis. Those with varying dissolution results were tested in small panels of human subjects. Where possible, in vivo/in vitro correlations were developed. These would eventually be used to establish dissolution specifications for the product so as to provide lot-to-lot bioequivalence assurance, once the bioequivalence to the innovator’s product had been established.

Because methodology development for topical products proved to be especially difficult, a number (where one could observe clinical efficacy) were allowed to be marketed with “deferral” of the bioequivalence requirement. The thought was that when methodology was developed, in vivo studies would then be required. With the passage of the 1984 amendment, the granting of deferrals ceased, as the amendment required a demonstration of bioequivalence for approval.

The biopharmaceutic regulations (17) specified that blood level and/or urinary excretion studies must be conducted when possible. When such studies were not considered to be feasible, alternative pharmacodynamic studies could be employed to demonstrate BA/BE. Should neither blood level/urinary excretion studies nor pharmacodynamic studies be feasible, full clinical studies were required. As pharmacodynamic measurements proved to be difficult to interpret, the only bioequivalence-based approvals using a pharmacodynamic approach employed the Stoughton–McKenzie test (for the topical glucocorticoids) (18–21). Attempts to use skin-stripping to develop a pharmacokinetic curve did not pass muster."

Texto tomado de Skelly JP. A history of biopharmaceutics in the Food and Drug Administration 1968-1993. AAPS J. 2010 Mar;12(1):44-50. doi: 10.1208/s12248-009-9154-8. Epub 2009 Nov 20. PMID: 19936940; PMCID: PMC2811644.