An Update On the Generic Drug Approval Process

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  • CLIN. RESEARCH & REG. AFFAIRS, 14(2), 139-154 (1997)

    AN UPDATE ON THE GENERIC DRUG APPROVAL PROCESS

    Michael R. Hamrell, Ph.D., President MORIAH Consultants

    Yorba Linda, California 92886

    ABSTRACT

    In 1984 the Drug Price Competition and Patent Term Restoration Act changed the regulatory climate for generic drugs. This law allowed for the approval of generic 'me-too' Copies of many approved drug after the patent had expired. Although the road has not been smooth, the generic drug approval process has had a significant impact on the availability of generic versions of approved drug. This article discusses the evolution and changes that have occurred in generic drug approvals since the 1984 Act.

    INTRODUCTION

    A generic drug is a drug product that is an identical copy in composition,

    formulation, strength, packaging, and labeling that is marketed by a company other

    than the company that did the original research on the drug product (the innovator firm)(l). These drugs are also often called 'me-too' drugs. The innovator firm

    will have completed many years of chemical development, preclinical animal

    testing and clinical testing in humans before gaining approval from the Food and

    Drug Administration for the product. Generic drugs on the other hand, do not

    139

    Copyright 0 1997 by Marcel Dekker, Inc.

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  • 140 HAMRELL

    undergo such extensive testing and are currently approved by FDA through an

    abbreviated application process.

    The drug approval process for generic drugs has evolved over the last 60 years as the Food Drug and Cosmetic Act has changed. In 1938, Congress amended the

    Food Drug & Cosmetic (FD&C) Act to impose a premarket approval requirement

    for new drugs. It also charged FDA with setting up rules and regulations for the

    interpretation of the new law. However, this premarket approval was only based

    on the safety of the drug. The FD&C Act was amended again in 1962, this time adding the burden of effectiveness to the drug approval process as well as safety.

    During the period of 1938 - 1962, a number of new drug products were placed on the market along with a number of Copies of these products. As a result of the new

    requkments for efficacy, the FDA determined it needed to evaluate the drugs on

    the market Pre-1962 that had never been evaluated for efficacy. It set up an administrative procedure to retrospectively review the drugs approved before 1962

    for efficacy. The Drug Efficacy Safety Implementation (DESI) Review was

    conducted to review the efficacy claims for all Pre-1962 drugs on the market. As

    a result of this review, a number of ineffective drugs were taken off the market, reformulated, or modified to meet the findings of the DESI Review (2).

    Since the DESI review had evaluated many copies or generic versions of pioneer drugs, the FDA established a policy in 1968 at the end of the DESI review that

    would allow for a shortened form of the New Drug Application or an

    'Abbreviated' NDA (ANDA) for the generic drug. For drugs found to be effective

    by the DESI Review, the FDA published the conditions under which an ANDA could be submitted to market an identical version of the product. Under the statues, the ANDA policy only applied to Pre-1962 drugs that had been reviewed

    by the DESI panel and found to be effective.

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  • GENERIC DRUG APPROVAL PROCESS 141

    During the 1960s and 1970s, many drug products were introduced onto the market

    and subsequently had their patents expire. The FDA policy however, did not allow

    for ANDAs for these drugs. In 1978, the FDA expanded the scope of its ANDA

    policy somewhat to include post-1962 drugs. The FDA concluded that if adequate

    published studies exist to support the safety and efficacy claims of a particular drug

    entity, another manufacturer of that post-1962 drug should not be required to

    conduct new studies to support the same claims. This would unnecessarily expose

    additional humans to risk, consume clinical resources and cause FDA to review

    duplicative studies. The FDA therefore adopted a policy for requirements for an NDA for a duplicative drug product for a post-1962 drug. This policy allowed for

    the submission of copies of published studies (scientific) concerning the safety and

    efficacy of the original drug product. This became known as the "Paper-NDA".

    The paper NDA was not widely used due to the lack of published literature on most

    post- 1962 drugs

    and was not considered a substitute for a full ANDA program that addressed all

    post-1962 drugs (3).

    The Drug Price Competition and Patent Term Restoration Act of 1984

    The need for a full ANDA program for post-1962 drugs led to the passage by

    Congress in 1984 of the Drug Price Competition and Patent Term Restoration Act. Also know as the 'Waxman-Hatch' Bill after its Congressional sponsors, the 1984 Law amended section 505 of the FD&C Act to allow for an ANDA for any generic

    version of an approved new drug (4). This was subject only to patent or

    exclusivity provisions that may exist for the product. In order to determine what

    new drugs were approved and their status, the FDA was required to publish a list

    of all approved drugs, their patent status and information regarding bioequivalence

    requirements. This information is available in the Approved Drug Products and

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  • 142 HAMRELL

    lhempeutc Quivalence Rating Book (Orange Book), published by the FDA on a monthly basis. In 1989 the FDA published regulations for implementation of the

    1984 Law, and the regulations were finalized in 1992. The regulations permit an

    ANDA only for a product that is the same as the listed drug with respect to active

    ingredients, route of administration, dosage form, strength, and conditions of use.

    Any modifications or deviations from the exact product must be submitted and

    approved in advance by the FDA through a suitability petition.

    Post 1984 Generic Approvals

    As a result of the passage of the Waxman-Hatch bill in September 1984, the FDA found itself dealing with a large backlog of demand for generic versions of post-

    1962 drugs that had long since been off-patent. In the first full year after the

    Waxman-Hatch took effect, the FDA's Office of Generic Drugs received over lo00 original ANDAs, compared to only 400 in 1983. This increased number of

    submissions continued for the next few years with 900-1200 applications received

    each year. In addition, there were a significant number of supplements to approved ANDAs covering changes that inevitably follow a large number of

    approvals.

    In order to meet this demand, the Office of Generic Drugs was given new

    expanded facilities

    within the FDA and additional reviewers were added to the staff. The

    Bioequivalence Branch in the Division of Biopharmaceutics was transferred to the

    Office of Drug Standards and made into the new Division of Bioequivalence to

    support the generic drug approval process. Overall, almost 50 new reviewers and support staff were added to meet the generic drug approval demand.

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  • GENERIC DRUG APPROVAL PROCESS 143

    Industry Challenges and Opposition to Generics

    The passage of the 1984 Law was a landmark in compromise legislation to satisfy

    the m n m s of two sides of the industry. The generic drug industry and consumer

    groups wanted generic versions of post-1962 drugs to be readily available. The innovator or pioneer drug firms were very much against the expansion of FDA's

    ability to approve ANDAs for generic versions of post-1962 drugs. Additionally,

    they wanted some regulatory relief from the valuable patent life 'lost' during the

    FDA review process. As a result, the 1984 amendment includes Title I1 that

    covers patent term restoration for the administrative and review time lost to the

    patent life of a product. In return for patent term restoration, the innovator firms

    conceded generic versions of post-1962 drugs.

    Although, the law changed the rules, many innovator firms found new ways to try

    to moderate the approval of generic versions for their drug products. These firms

    mounted legal challenges to FDA's approval criteria, submitted petitions charging

    bioinequivalence of generic versions of their products, poor manufacturing

    compliance by generic firms, and arbitrary, inconsistent suitability decisions by

    FDA. They also started an advertising campaign to 'alert' the public to the

    dangers of non-equivalent versions of their medicines (5). When a company was

    unsuccessful in stopping the FDA approval for a generic version of its product,

    they took their challenges to state and hospital formulary boards with some degree

    of success.

    In an effort to gather information on claimed problems with FDA's Bioequivalence

    program, and with generic drugs in general, the Agency sponsored a three day

    informal public hearing in September 1986 in Washington, D.C. The Hearing

    consisted of five sessions on topics related to the issue of bioequivalence of

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  • 144 HAMRELL

    immediate release solid oral dosage forms drug products. Despite a noted lack of

    scientific data to back many of the concerns expressed regarding bioequivalence

    testing, the meeting was attended by more than 800 representatives of academia, industry, the medical profession and government. Following the Hearing,

    Commissioner Young appointed a Task Force to analyze the issues raised at the

    Hearing and the comments submitted to the Public Docket. The purpose was to

    make recommendations to the Agency for action it should take in response to the

    comments conceming the Bioequivalence Program. The Task Force Report, issued

    in February 1988, concluded that the underlying fundamental principle, that drug

    products delivering comparable blood levels of a therapeutic substance yield

    comparable therapeutic results, was scientifically sound and that it saw no need to recommend major changes in the way FDA approves generic drug products. The

    report supported the long-standing policy that if a drug product is declared by the

    Agency to be therapeutically equivalent, a physician, in managing a patient, can feel secure that authorizing a substitution of that product for any other generic,

    therapeutically equivalent, product will provide the same intended effect (6).

    The passage of the Waxman-Hatch Bill had opened the market for the approval of

    generic versions of many top selling drugs developed post-1962 whose patent had

    expired. The potential generic market was estimated at over $900 million dollars

    and growing, as insurance companies, managed care providers, and the government tried to control the costs of health care. This broad new market stirred the development of many new generic drug manufacturers, as well as leading to the expansion of many older, established ones. The competition to be the fust generic version of a product on the market was seen as key to penetration into the market and quick cost recovery for the generic manufacturer,

    The FDA was receiving well over lo00 ANDA applications each year for generic

    versions of drug products. Along with supplements, amendments, suitability

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  • GENERIC DRUG APPROVAL PROCESS 145

    petitions and citizen petitions challenging FDA's policy, the Generic Drug group

    was overworked and understaffed. In an effort to speed up the generic drug

    approvals, an em of openness between FDA and industry existed that saw industry

    regulatory representatives fresuently visit the FDA reviewers in an effort to rapidly

    deal with any issues that came up during the review of an ANDA. As a result, a few companies tried to seek an edge in this highly competitive marketplace.

    The Generic Drug Scandal

    In late 1987, one company became increasingly concerned that their applications,

    which were apparently submitted earlier than other companies, were delayed and

    acted upon after the applications submitted later. Company representatives took

    their concerns to the Director of the Division of Generic Drugs at FDA who

    dismissed them as unfounded. Still convinced of a problem at FDA, the company hired its own private investigator to look into the allegations. What the

    investigator uncovered would subsequently shake the generic drug industry, and the

    FDA, with a major scandal of significant proportions.

    The investigator discovered initially that one FDA Chemist in Generic Drugs was

    receiving large gifts of money and furniture at his home. The items seemed to be

    coming from persons associated with a small generic company that had recently received some first generic approvals. The company this time took their evidence

    this time to Congressman Dingell, a longtime critic of FDA, and Chairman of the

    House Oversight and Investigations Subcommittee on FDA. As a result of this

    evidence, the Secretary of HHS took the unusual step of alerting the Inspector General's Office, and an immediate investigation of the FDA Generic Drug

    approval process and personnel associated with the process was begun. Offices

    were sealed, records and notes gathered as evidence, and key staff members were

    interviewed. The Inspector General and US Attorney's office began looking into

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  • 146 HAM R E L L

    the allegations for the fist time. Much to their dismay, the allegations appeared

    true. It appeared that some companies had tried to subvert the integrity of the review process by paying bribes and kickbacks to a few FDA reviewers for either

    favorable or more timely reviews.

    At the same time, in response to growing allegations of problems and

    inconsistencies with the generic approval process, the FDA changed policy on

    industry meetings, increased training in the area of conflict-of-interest and ethics

    for government employees, and increased management review of all pending

    ANDAs. Additional FDA reviewers and support staff were now under

    investigation and were transferred from Generic Drugs. In April 1989, the US Attorney announced criminal indictments against two FDA reviewers and a number

    of generic drug industry representatives. This was the first of many indictments

    to follow. The Commissioner immediately called for a complete audit of the

    generic drug program by the Inspector General. The FDA also began an inspection

    of all generic drug firms for possible compliance problems, focusing on certain

    companies accused of illegal activities.

    As the extent of the illegal activity began to unfold, the participants involved began

    to fall. One company official pleaded guilty to giving an unlawful gratuity to an

    FDA official. Two FDA reviewers pleaded guilty to accepting bribes and

    racketeering. Three other FDA persons were removed from their positions, two

    subsequently plead guilty to accepting bribes. The other, the Director of Division

    of Generic Drugs, would later be convicted of accepting illegal gratuities from

    company officials and perjury (7).

    The problems did not occur with a only few dishonest FDA reviewers and

    company officials. As a result of the audit of generic drug manufacturers, it was

    uncovered that there was major problems in the manufacturing compliance part of

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  • GENERIC DRUG APPROVAL PROCESS 147

    the generic drug approval process. Apart from overt instances of fraud and

    misrepresentation, a number of companies were found to be out of compliance in

    their manufacturing operations. This included unapproved changes to

    manufacturing processes, lack of quality control procedures, use of unapproved

    raw material suppliers, as well as many other manufacturing problems. Following

    extensive inspection and investigations, over 50 products were withdrawn from the

    market due to questions about the integrity of the application. Another 75 products

    were voluntarily recalled to correct deficiencies in GMP procedures.

    To deal with the issues raised by the generic drug scandal, the FDA announced in

    late 1989 an action plan to ensure the safety and effectiveness of generic drugs.

    This included intensified inspection programs for generic manufacturers,

    reorganization of the generic drug review process, a strengthening of the

    relationship between the FDA and Inspector General's office, and new resources

    for intensified surveillance activities. The FDA also issued a set of revised Policy

    & Procedures guides to the review staff for the handling of ANDAs. Additional

    staff were hired in Generic Drugs to help with the workload as well. Finally, in

    early 1990, as a result of mounting pressure from the industry to obtain outside

    input into the generic drug process, the FDA announced the establishment of a

    Generics Drug Advisory Committee. In addition, the Agency transferred the

    authority for generic drug approvals from the Office of Drug Standards to the new

    Office of Generic Drugs.

    The inspection of generic drug manufacturers prior to approval of an ANDA

    revealed that not only did generic manufacturers have GMP compliance problems,

    but many innovator firms did as well. Many firms did not have complete

    validation procedures in place, lacked adequate QC and sampling routines, and

    many other examples of manufacturing controls that would ensure the quality and integrity of drug products produced. The inspectional experience also revealed that

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  • 148 HAMRELL

    there were many discrepancies between what some generic firms submitted to the FDA and their actual manufacturing operations. The FDA's observations,

    although based largely on the generic industry, also included some innovator firms. The Agency felt that additional inspections were warranted to audit application

    commitments and statements against actual manufacturing practices used by

    applications before final marketing approval was granted. As a result, the FDA

    expanded the policy on inspections for new drug applications, and made a Pre-

    Approval Inspection (PAI) of the manufactwing plant a requirement for final NDA or ANDA approval (8). This policy was proposed and implemented provisionally in 1991, and finalized in 1993. As a result of this program, many NDA and

    ANDA approvals were delayed while firms completed validation and testing

    procedures to document their manufacturing operations. A number of firms had

    much difficulty meeting FDA's criteria for GMP compliance prior to granting

    approval for a product. The need for better written Chemistry and Manufacturing

    sections of applications, full quality assurance procedures and good documentation practices was clear from FDA's inspectional observations. Companies that could

    demonstrate a clear understanding of GMP regulations and a fully implemented

    compliance program were able to pass a PA1 while those f m s that did not have

    procedures and processes in place often had much difficult with FDA inspections. Another area of concern during the generic scandal was the admission by one company that it had substituted the innovator's product for its own in

    bioequivalence testing. In attempting to audit the bioequivalence study and data,

    no samples had been retained by the company or the testing lab to validate what

    drug product had in fact been used in the testing. The FDA realized that there was no specific requirement in the regulations to require retention of bioequivalence samples for such purposes. As a result, the FDA issued an interim rule in

    November 1990 (later finalized in 1993), immediately requiring firms to retain

    samples of all drug products used in bioavailability and bioequivalence testing for new drug applications (including abbreviated NDAs) (9).

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  • GENERIC DRUG APPROVAL PROCESS 149

    In January 1992, Congress passed a bill to establish procedures to restore and

    ensure integrity of the ANDA approval process and to bar individuals convicted of

    crimes pertaining to the regulation of drug products from working for companies

    that manufacture and distribute such products. Known as the Generic Drug

    Enforcement Act of 1992, the law adds a new section to the Food Drug and

    Cosmetic Act. The law authorizes FDA to debar any individual or firm, convicted

    of certain crimes or found to have engaged in certain types of conduct, from

    providing services to any drug product applicant (10). The new laws applies not

    only to ANDAs, but also to NDAs, AADAs, NADAs, ANADAs, PLAs, and

    export applications for certain unapproved products. All applications submitted

    after the effective date of the law must now contain a statement that no individual

    debarred from the drug approval process has participated in the preparation of the

    application. The FDA can also under this law, deny temporarily approvals of

    ANDAS for any lirm if the sponsor is under criminal investigation. The FDA can

    also suspend the approval of a generic company's products if it can demonstrate to

    a judge that the approvals were tainted by repeated misconduct. This misconduct

    may include a "pattern of practice" of making false statements to the FDA, or

    having committed "flagrant and repeated" GMP or GLP violations during a short

    time period. Finally, the law also includes civil penalties of up to $250,000 for

    individuals and $1 million for corporations for fraudulent activities (1 1).

    The final toll for the generic scandal included five FDA officials were either

    convicted or pleaded guilty to various crimes, more than 28 company officials from various generic companies were convicted of bribery, fraud, obstruction of justice,

    racketeering and other crimes. A number of generic companies were put out of

    business as a result of these activities. Companies and guilty officials paid a record

    over $18 million in fines and penalties as a result of the government's

    investigation. It was clear that the FDA approval process and the generic industry

    would never be the same again.

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  • 150 HAMRELL

    ANDA Review Process

    The review process for an Abbreviated New Drug Application (ANDA) is similar

    in many respects to the review for an full New Drug Application. After receipt, the ANDA is reviewed for acceptability and completeness. Under FDA's 'Refusal to

    File" Policy, incomplete or unacceptable applications can be refused for

    consideration by FDA. In addition the FDA confirms that the application

    references the proper 'listed drug' for that product or contains information that a

    suitability petition for a variation has been approved by the FDA. Each ANDA must also contain a patent certification, a statement that either no patent is in effect for the product (or will expire on a certain date), or that the application uses a

    product or process that does not conflict with the patent (12,13).

    The format of the ANDA must follow the general requirements for NDA

    submissions as a result of the 1985 NDA rewrite, with a blue archival copy and a technical review copy. In addition, as a result of the PA1 program, an additional copy of the manufacturing and controls section must be submitted in a separate

    binder for distribution to the regional FDA Office for use by the investigators during the Pre Approval Inspection.

    Once an application is approved, certain types of changes to the approved application must also be sent to the FDA for review and approval. This may

    include a change in manufacturing information, supplier, or formulation changes.

    These changes must be formally submitted to the FDA as a supplement to the

    approved application. The types of changes that require prior approval by FDA

    are clearly defined in the regulations and the recent guideline on Scale Up and Post Approval Changes (SUPAC) (14).

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  • GENERIC DRUG APPROVAL PROCESS 151

    Generic Drugs Workload

    Prior to the generic scandal, from 1984 to mid-1988, the Division of Generic

    Drugs received an average of 80 - 100 original applications per month for generic

    drugs. Actions on applications was averaging around 200 letters per month during

    this same time period, with 30-40 original approvals granted each month. This

    high workload and the pressures of keeping up may have contributed to the

    problems associated with the generic scandal.

    Immediately following the revelations of the generic scandal, the FDA severely

    restricted approval of new applications and supplements until they were sure of the

    integrity of applications and the companies involved. Likewise, companies stopped

    submitting ANDAs knowing that FDA was not acting on applications in the wake

    of the scandal. By early 1989, the number of applications received had dropped to

    30-40 per month while approvals had dropped to less than 10 per month, with

    some months having no applications approved. As the FDA tried to sort out the

    problems, action letters also dropped significantly with only a handful being issued per month on average. This trend continued through 1990 and into 1991 as the FDA slowly sorted out the process, instituted changes, and instituted new

    procedures and programs to ensure the integrity of the application process (15).

    One of the biggest impacts on the generic drug approval process was the implementation of the Pre-Approval Inspection program (described earlier). As

    a result of this program, the FDA found that a significant number of firms were

    not in compliance with GMP requirements, had numerous undocumented and

    unapproved changes for approved applications, and an overall lack of

    understanding of GMP practices. This lead to a very high level of review and

    scrutiny of the chemistry, manufacturing and controls sections of applications.

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  • 152 HAMRELL

    Additionally, due to the evidence of fraud found in the application process, both

    innovator and generic companies are required to provide certification that they did

    not use any debarred individual in any capacity in the application.

    The heightened emphasis on GMPs and compliance by FDA led to a distinction

    between the quality of submissions from various generic manufacturers. Most of

    the generic firms had high quality operations, and good documentation and GMP

    practices. For these firms, the new emphasis on GMPs was just another item to deal with in order to gain approval of their products. A few other firms had been

    operating with the best of intentions, but their operations were deficient in many

    areas. For these firms, the emphasis on GMPs caused them to spend a great deal

    of time, effort, and often money to get their manufacturing operations and

    documentation up to the new standards expected by FDA. As a result, approvals

    were held up or delayed for a significant time period while the firms complied with

    the FDA standards for GMPs and pre approval inspections. Finally ,there was a

    very small number of firms who, despite all of the problems in the recent years in

    the generic industry and FDA's expectations, tried to do business they way they

    had before. These few firms repeatedly failed pre approval inspections, did little

    or nothing to address the issues raised by the FDA, refused to comply with FDA requests for additional information, testing or documentation, and often argued that

    FDA's demands were unfair and should not apply to them. These pleas of

    unfairness fell on deaf ears, and did not gain much sympathy from the public, FDA, or Congress. Given the level of scrutiny being placed on FDA, the generic

    drug industry, and the individuals involved, there was little hope of any leniency being granted. These few firms found out very quickly to either comply with

    FDA's new expectations and demands regarding GMP compliance or they would

    go out of business.

    Since the changes in the Office of Generic Drugs have been implemented and

    incorporated, the workload has returned to a level that approximates the pre-

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  • GENERIC DRUG APPROVAL PROCESS 153

    scandal level. Although the rate of review and action letters has returned towards

    earlier levels, the level of scrutiny of applications has remained higher.

    summary

    The approval of Generic Drugs by the Food and Drug Administration has made a

    significant impact on the availability of generic versions of many leading drugs.

    Although the regulatory approval system for these drugs has suffered through a

    major scandal and a lack of confidence, it still continues to approve generic drug

    products. These products are required to meet the FDA standard for a new drug

    product, and generic drugs are subjected to the same rigorous standard for approval

    as innovator products. Despite much discussion and attempt to prove otherwise,

    generic drugs are approved based on bioequivalence requirements that support

    interchangeability and substitution.

    REFERENCES

    1.

    2.

    3.

    4.

    5.

    6.

    7.

    Food and Drug Law. ed. Richard M. Cooper, 1991. pp. 249-252,

    Food and Drug Law; Case Materials. eds. Memll & Hutt, 1980. pp.370- 378.

    NDAs for Duplicative Drug Products of Post-1962 Drugs. FR 46:27396, 1981.

    Pub. L. NO. 98-417, 1984.

    The Big Lie about Generic Drugs. Consumer Reports, 52(8):480-487, 1987.

    Report of the Bioequivalence Task Force on Recommendations from the Bioequivalence Hearing Conducted by the Food and Drug Administration, FDA, January 1988.

    Ander, G, Rumore, MM, Torre, GM, and Hyman, L. Major Consequences of the Generic Drug Scandal of 1988., Regulatory Afuirs 6: 137-159. 1994.

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  • 154 HAMRELL

    8. New Drug and Abbreviated New Drug Applications; Preapproval InSpection Requirements; Final Rule. FR 58:47340-47352, 1993.

    9. Retention of Bioavailability & Bioequivalence Testing Samples; Final Rule. FR 58:25918-25928, 1993.

    10. Generic Drug Enforcement Act of 1992. Pub. L. 102-282, 1992.

    11. Civil Money Penalties: Biologics, Drugs, and Medical Devices; Proposed Rule, FR 58:30680-30689, 1993.

    12. Abbreviated New Drug Applications, Final Rule. FR 57: 17950-18001, 1992.

    13. Understanding and Preparing ANDAs. Speech given by David Rosen at RAPS Seminar, July 1987.

    14. Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval Changes (SUPAC) Notice. FR 60:61638, 1995.

    15. Generic Drugs: A New m. Speech Given by Roger Williams at RAPS Annual Meeting, September 1991.

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