Federal Regulation of Medication Production

Function

Even though the government passed the first law safeguarding the public from food and pharmaceuticals in 1906, the present-day FDCA was not passed until 1938. The 1938 rule stipulated that drug items that were not already on the market may not be commercialized until these medications were demonstrated to be safe. In addition, drug labels must include proper instructions for use and caution. Several legislations and laws followed to functionalize the pre and post regulations in enactment today:

• The Prescription Drug Marketing Act (PDMA) of 1987 created prescription drug sample distributions and prohibited hospitals and other healthcare bodies from reselling medications to other enterprises.
• The 1984 Patent Term Restoration Act (PTRA) streamlined the approval system for generic pharmaceuticals while allowing innovator drug items to keep their patents.
• The Orphan Drug Act of 1983 incentivizes drug and biologic producers to discover and sell treatments for uncommon diseases and illnesses.
• The 1962 Kefauver-Harris Amendment added a requirement for the efficacy of drug products proven with substantial evidence, made retroactive to 1938. Drugs that were on the market before 1938 were exempt.
• The Durham-Humphrey Amendment defined two classes of drugs: prescription and OTC. 
• Producers must pay application fees for NDAs under the Prescription Drug User Fee Act (PDUFA) of 1992.[4]
• The Dietary Supplement Health and Education Act (DSHEA) of 1984 established dietary supplements and mandated the FDA to regulate them more like foods than medications.
• The Food and Drug Administration Modernization Act (FDAMA) of 1997 facilitated regulatory procedures to speed up medication and device availability and established a fast-track approach for medications designed to treat critical or life-threatening conditions.
• The Food and Drug Administration Amendments Act (FDAAA) of 2007 gave the FDA much more power to oversee drug safety, including requiring Risk Evaluation and Mitigation Strategies (REMS) when appropriate.
• Among other measures, the Food Administration Safety and Innovation Act (FDASIA) of 2012 introduced user fees for generic pharmaceuticals and biosimilars.
• The Drug Quality and Security Act (DQSA) of 2013 simplified the law on pharmacy compounding, introduced track and trace rules for prescription medications, and made a novel sterile compounding entity termed "outsourcing facilities."
• The Cures Act of 2016 facilitated and expanded the drug development and approval systems, enabling other patients to experience data collection along the way.[5]

The FDCA's principal purpose is to safeguard the public, but there is a trend toward indirect control rather than direct regulation.

Issues of Concern

In the 1980s, when an NDA cleared a new chemical entity, the market exclusivity provision mildly secured the production rights to the generic drug for five years. In other words, the FDA did not sanction a generic drug application for another five years from the approval date for a drug. In cases where a new drug has clinical significance, the FDA may also grant three years of exclusivity regarding the investigations. The FDA, however, used to hold the right to sanction further Abbreviated New Drug Applications (ANDAs) for other drugs. Even though the FDCA allows generic businesses to obtain regulatory approval for medications by submitting an ANDA, it was evident in the early 1980s that there were relatively few generic medications in the marketplace. The US Congress looked into the matter and discovered that it was easy for innovator businesses to make it hard for generic companies to submit ANDAs under pre-existing patent and regulatory law. The regulatory road for getting ANDAs approved was erratic and ambiguous. The Patent Term Restoration Act (PTRA) of 1984, also known as the Hatch-Waxman Act, was drafted and passed in retaliation. The PTRA, however, led to various controversies.[6]

Practitioner Controversy

Firstly, the legislation enables a generic drug to differ from the parent medicine by 20% more or less in rate and endurance limit while still being considered bioequivalent. Some physicians, therefore, started believing that if a patient takes generic X for one month and then uses generic Y for the next month, there might be a 40 percent blood level differential between the two products, resulting in adverse clinical effects for the patient.

• In public pronouncements, the FDA addressed this worry by stating that the statistical approach in question would not permit such a variation.
• When evaluating data on generic medications authorized between October 1984 and September 1986, the FDA further stated that the mean variation in absorption between generic and pioneer medications was just 3.5 percent, which should not result in clinical disparities in patients.
• Nonetheless, several medicinal items are still the subject of debate.[7]

Secondly, the statute also sparked a debate about whether physicians might prescribe a generic drug product and dispense them if the innovator drug product obtains exclusivity. For instance, when the original brand propranolol has commercial exclusivity for that application, can a pharmacist legally replace generic propranolol given for post-myocardial infarction? Since this is the use of an approved drug (the generic medicine) for an off-label reason, the basic answer to this issue is "yes."

Manufacturer Controversy

The PTRA has resulted in some highly contentious drug manufacturing methods. Several of these activities have existed since the act's inception. Still, they also have come to the attention of Congress and the public in recent years as a result of the current expiration or impending expiration of numerous bestselling medication patents.

One such method involves an innovator manufacturer creating an "authorized generic" variant of its brand-name product just before its patent is due for expiration or is successfully challenged by a generic competitor. Since generic and brand-name prescription drugs are alike and thus approved under the NDA, the FDA believes the innovator may do so without an ANDA, meaning the innovator manufacturer may create the generic and compete with a generic manufacturer who has submitted an ANDA with a successful paragraph IV certification. The 180-day market exclusivity is no longer as valuable to the generic producer, and the innovator company keeps some market share that they would lose in other ways.[8]

Another point of contention is the 30-month delay in ANDA clearance after the patent holder files a patent infringement civil lawsuit against the generic firm. Many innovator producers, according to critics, sue to secure the 30-month exclusivity despite their poor legal claims. While new legislation has restricted this procedure, several vendors have piggybacked cases to allow for extended 30-month exclusivity terms.

Generic Drug Labelling Controversy

The PTRA stipulates that a generic medication's marking must be identical to that of the innovator drug (355(j)(2) (A)(v)), which has sparked considerable debate. For example, in Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996), Bristol-Myers Squibb Co. retained exclusivity rights to an indication accepted through a supplemental application for one of its drugs products for three years.

• A generic manufacturer submitted an ANDA for a generic alternative of Bristol-Myers' product. Bristol-Myers contended that the ANDA be refused because the law demands that the generic marking be identical to that of the innovator, which cannot be due to Bristol-Myers exclusivity privilege.
• However, the court concluded that the manufacturer's view is inconsistent with other aspects of the legislation and statutory purpose. The new generic drug must be safe and effective with each use mentioned in the labeling.
• It makes no difference that the marking does not have any sign specified on the pioneer's label. But, because every time a company introduced an additional indication, the authorities barred a new generic drug product from the market for three years, the Bristol-Myers understanding emerged.
• An innovator drug product producer could theoretically file additional indications for years, effectively preventing generic contests.[9]

Pliva, Inc., et al. v. Mensing, 131 S. Ct. 2567, a 2011 Supreme Court case, led to a vital turn in the debate over similar generic medicine labeling. In this case, the plaintiffs were damaged by a medicine's side effect. They sued the generic drug maker, claiming that the manufacturer owed them a duty to modify the labeling to indicate the known side effect. A CBE additional NDA allows a medication manufacturer to make certain adjustments, such as warnings, before FDA clearance. In a 2009 case before the United States Supreme Court, the Court said that an innovator drug's maker could have updated its labeling under the CBE supplementary NDA to reinforce its warnings and ruled for the injured plaintiff (Wyeth v. Levine, 129 S. Ct. 1187 (March 4, 2009)). However, in Pliva, the Court determined that generic medication manufacturers are prohibited from freely changing their labeling and consequently ruled against the injured plaintiff, based on the FDA's understanding of the labeling rule.[10]

Clinical Significance

Ever since the passage of the FDCA, clinical efficacy proven by authentic empirical methods has played a significant role in the development of federal protocols about medication production. 

• An entrant must produce evidence (under 505(d)) that the medicine is safe and efficacious when requesting clearance for an NDA. 
• Animal and clinical (human) investigations are required as evidence. 
• Section 505(a) prohibits the distribution of any novel medicine unless it has been FDA approved. 
• 505(i), which permits the FDA to exempt a medication from the NDA criteria for clinical research, avoids this seemingly conflicting position. 
• The maker must file a "Notice of Claimed Investigational Exemption for a New Drug," also known as an Investigational New Drug (IND) Application, to get this exclusion. 
• The producer could then perform clinical tests of its IND if it is authorized.
• The filing of an IND follows the applicant's lengthy preclinical inquiry. The petitioner has decided that the drug has prospective worth and would be reasonably safe to try in people through laboratory experiments and animal testing.[11]

Biological products act as a paradigm example; these products have been under government regulation since 1902 and are now governed by the FDCA, and the Public Health Service Act (PHSA) since the Affordable Care Act (ACA) of 2010 codified them as drugs.

• To be considered interchangeable, the applicant must show that the biosimilar will deliver the same clinical outcomes as the reference product while posing no additional risk.[12]
• Biologics are items made from living organisms used to treat, protect, or heal human diseases or conditions.
• As part of the ACA, the Bundled Payments for Care Improvement Advanced (BPCIA) allows the FDA to approve biosimilar products.[13]
• Biosimilarity refers to how closely a biological item resembles a reference product with no clinically significant deviations.

Other Issues

The word "drug" has a very loose interpretation underneath the FDCA, which involves any article designed to treat illness or alter the structure or function of the human body. Various legal clashes may derive from such interpretations.[14]

• Depending on its desired use, a cosmetic may be classified as a drug, and courts would most possibly use the naive, unthinking market criterion to make this decision.
• A few items are both cosmetics and medications.
• Foods are not classified in Part C of the substance specification, which raises the question of what constitutes food for the objectives of Part C.
• If they are sold to fulfill specific health requirements and can be prescription only, foods that come in the category of "limited nutritional foods" or "medical foods" are not considered medications.[15] 

• If food makes disease or health claims, this could be a drug whether the claim is authorized by FDA regulation or by "significant scientific agreement."

• Dietary supplements were described and developed by the DSHEA as a distinct product category. 
• Without violating Part C of the medication definition, a substance that fits the legal description of a dietary supplement can make four kinds of nutritional support claims. 
• Since the claim meets the substantial scientific consensus requirement, a substance that fits the legal meaning of a dietary supplement could create an "unqualified" health or disease claim without classifying a drug if the FDA accepts the claim via regulation. 
• Even if the argument does not satisfy the substantial scientific consensus test, a substance that fits the legal meaning of a dietary supplement could make a "qualified" health or disease claim if it is not deceptive.[16] 
• If the dietary supplement was authorized before the prescription, dietary supplement products containing medications are almost certainly drugs. 

• As the ephedra product case shows, the FDA will only take a dietary supplement off the market if it can claim it is diluted, which means it poses a severe or unfair risk of disease or accident under the DHSEA.
• The 2006 Dietary Supplement and Nonprescription Drug Consumer Protection Act mandates dietary supplement and nonprescription medication distributors to warn of severe side effects. 
• DSHEA is now under criticism for preventing the FDA from testing dangerous goods before market introduction and making it extremely difficult for the regulator to withdraw hazardous items from the market. 
• Since 2007, the FDA has mandated that dietary supplements follow the Good Manufacturing Practices (CGMP) to avoid misbranding and spoilage and determine the identification, authenticity, consistency, weight, and composition of their drugs. The FDA, on the other hand, has no power to test medications until they are marketed.[9][13]
• The line between product and medication can overlap. For example, a device may be classified as a drug depending on its intended use; however, the MDA usually grants the FDA some power to control devices without going too far. 
• The United States Pharmacopeia (USP) and the Homeopathic Pharmacopeia of the United States (HPUS) are official compendia under the FDCA. 

• The USP establishes drug regulations, and the HPUS regulates homeopathic products. 
• Homeopathic drug products will be subject to risk-based preference compliance by the FDA.[17]

Enhancing Healthcare Team Outcomes

The FDA has a voluntary reporting system called MedWatch that enables healthcare providers to report any significant abnormalities, prospective and existing product use faults, and product quality issues involving pharmaceuticals, biologics, medical devices, unique dietary items, and cosmetics the organization. The Access Data web platform has an official reporting form (FDA 3500) that may be viewed and filled online. Pharmacists are the ones who report the most adverse medication reactions, and they're also encouraged to report any issue with a drug, such as incorrect labeling, the existence of foreign or particle matter, improperly made dosage forms, aberrant color or taste, and doubtful durability.[18]

The FDA, however, stresses interprofessional responsibility by asking healthcare practitioners to have a moral obligation to report suspected adverse events, product quality issues, and product faults to the organization. The Food and Drug Administration Amendments Act (FDAAA) of 2007 has expanded the scope of the MedWatch program to include patient feedback, which was initially meant for medical practitioners.[19]

The organization encourages practitioners to file reports, emphasizing that a report is neither a legal claim nor an admission that an adverse event, issue, or error has occurred. The practitioners' and patients' identification are kept private. In addition to medication, biological, and device reports, the FDA asks professionals to report information with descriptions of clinically significant toxicity linked to consuming large amounts of nutrients or food elements in nutritional supplements, such as vitamins and minerals.[19] The FDA also tends to look for serious, well-reported nonmicrobiological responses to food and food additives. The MedWatch program enables reporting and gives various product safety data, which professionals can find on the FDA's official website's safety page.[18][20]

Nursing, Allied Health, and Interprofessional Team Interventions

Although the FDCA § 301 is mainly self-explanatory, pharmacists should pay special attention to particular portions. 

• A pharmacist is prohibited from making, selling, or holding for sale or filling a counterfeit medicine under Section 301(i)(3). 
  • Counterfeit pharmaceuticals are a serious concern in the United States. This section lays out the pharmacy's and pharmacist's responsibilities for ensuring an ethical drug distribution network and the pharmaceuticals they buy and dispense.[21]

• Pharmacists who rebrand or relabel prescription or over-the-counter medications must pay special attention to section 301. (k).
• The pharmacist could be penalized with mislabeling if the new label does not meet FDA criteria in every detail.
• Pharmacists must double-check that the relabeled drug's label includes the same data as the manufacturer's label.[22]
• Recognizing which medication goods have been withdrawn is the responsibility of a pharmacist.
• Since the product is likely contaminated or mislabeled, distributing a recalled product may contravene the FDCA, creating difficulties for a pharmacist on claiming a good faith defense. 
  • In the case of a patient injury, the pharmacist may be held civilly liable.[22][23]

A drug is misbranded if it is offered underneath the title of another drug, according to Section 502(i)(3) of the FDCA. 

• The meaning of a counterfeit drug (§ 201(g)(2)) in sections 502(i)(2) and 502(i)(3) are very similar (3).
• A pharmacist who delivers a generic medicine while labeling using trade name drugs could be found in violation of both 301(i) (3) and 502(i) (3).
• A pharmacist who delivers a placebo branded as a specific drug may have also broken Section 502(i) (2) along with the other two provisions. 

The FDA believes that professional labeling data should exclusively appear safely with the supervision of a registered physician. 

• With the exception that the patient specifically wants it, a pharmacist should not offer professional advice to a patient, even though the manufacturer supplied the data to the pharmacist.
• The physician may receive the labeling from the pharmacist.
• Even though a pharmacist can offer an OTC drug to a patient for an ailment or dosage that is not label-indicated, doing so can expose the pharmacist to civil litigation if the patient is injured. 

The FDAAA obligated the FDA to create and nurture a centralized and easily retrievable website for patients and professionals, which included personal and healthcare labeling, latest safety data, details about enacted REMS, medication safety directives and regulations, and drug-specific overview assessments of malignant drug reaction findings, among other things. http://www.fda.gov/Drugs/DrugSafety/PostmarketdrugsafetyInformationforPatientsandProviders/default.htm is a precious asset for professionals and patients looking for drug details.[24]

The FDA released a risk management development vision in September 2009, recognizing the significance of discussing the risk to healthcare practitioners, patients, and users regarding all FDA-regulated goods. (https://www.fda.gov/aboutfda/reportsmanualsforms/reports/ucm183673.htm). The agency's attempts to disclose communications are outlined in this program, including pharmacists as a focal population for receiving the data.[25]

• Due to the lack of state regulation of nutritional supplements by the DSHEA, pharmacists play a critical role in supporting customers with correct product details and supporting them with product purchases. 
• If at all possible, pharmacists must direct patients to goods that comply with USP or NF criteria, or at the very least items whose producers can testify to purity and homogeneity criteria.
• Pharmacists must avoid promoting nutritional supplements based on unregulated health or illness statements since this can violate the FDCA. 
• It is perfectly permissible for pharmacists to advise, teach, and encourage health regarding the usage of a supplement for an illness, however. 
• DSHEA allows pharmacists to exhibit specific documents connected with the distribution of food additives, such as journal articles or excerpts from peer-reviewed medical journals. 
• To comply with the law, these papers should be reproduced in their totality; they should not be untrue; they should be portrayed with other articles published about the good or service, if accessible, to present a balanced perspective; they must be distinct from the original product, and they should not have any data attached to them by label or other technique.[26]

Prescription medication marketing from the producer to the customer, or DTC, emerged in the 1980s, breaching a practice of primarily marketing prescription pharmaceuticals to health care providers. 

• Pharmaceutical companies are increasingly using direct-to-consumer advertising, which has sparked a lot of debate.[27] 
• DTC marketing, according to supporters, helps consumers by offering information, increasing awareness of possible health risks, boosting medication therapy compliance, and decreasing prescription prices. 
• According to advocates, pharmacists may gain from increasing prescription revenue and public attention as the most competent and available source of extra prescription medication data.
• Opponents of direct-to-consumer advertising argue that it would increase health care expenses, create an unreasonable demand for pharmaceuticals, mislead patients, and undermine the physician-patient connection.[28][29][30]