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Indian Pharma and FDA Regulations in USA

Indian Pharma and FDA Regulations in USA

As a consequence of the US FDA tightening noose around the drug companies for violations of best practices, the Indian pharma industry is at present in a turmoil. While the importance of an effective regulation in the drug business cannot be doubted as slightest of a compromise can lead to serious consequences, the Indian drug companies are bracing themselves for the challenge. Read on to know more.

India is the largest supplier of medicine to the US. But, of late, Food and Drug administration (FDA) of the US has been serving Indian drug companies notices resulting in rejection of their supply to the US market. In February this year, the US drug and food regulator, issued Form 483 observations to Indian pharma major Glenmark. The US regulator inspected Glenmark’s Indore (Pithampur) plant in Madhya Pradesh and reported three major objections. However, the Indian drug company responded totheir objections and addressed the concerns raised by the FDA, and subsequently received product approvals from this plant and the export from this unit was allowed to the US.

It is not just Glenmark, in fact, many companies such as Wockhardt, Sun Pharma, Lupin, Ipca are currently facing problems with the US FDA. And all of them are not as fortunate as Glenmark which finally got the clearance from US FDA for the supply of medicines. According to an Indian industry chamber report, the annual growth rate in pharmaceutical exports may almost halve to 7.98 % by 2020 from 14.77%CAGR during 2010-2014.

USA is home to the generics from India. India has been supplying them with generics at a price which is too attractive for them to ignore. But the issues with the Indian companies in terms of quality, safety, compliance, etc. have been cropping up in the recent past. So, lets us try to understand what really are compliance issues? What system does FDA follow? What laws in the US deal with manufacturing and import of medicines to USA? What does the FDA really want from the India companies and how can Indian companies get over this issue nagging Indian pharma sector?

US FDA: THE REGULATORY AUTHORITY OF USA

The importance of an effective regulation in the drug business cannot be doubted because compromise can lead to serious consequences. The FDA, the primary regulator of medical products in the US, requires every new drug, including generic drugs, to be safe and effective. While the FDA does not develop, manufacture or test drugs, it requires evidence of a new drug’s safety and effectiveness, demonstrated through non-clinical trials and clinical trials of the drug on human volunteers, before it will approve a drug for marketing.

Before any drug is allowed to market in the US, FDA has to be informed of the drug’s detail such as chemistry, manufacturing, clinical data, etc., in order for the FDA to determine whether the drug is safe and effective for its proposed indication and it does not present risks that are disproportionate to its benefits. FDA also wants to know what information should be included in the drug’s labeling, and whether the manufacturing methods and quality controls are adequate. The FDA has to make sure that the medicines are wellmade as specified by the company in its pharmacopoeia and the manufacturers have complied with the standard procedures.

Medicine registration, or licensing and authorization are also important part of FDA regulations. The companies that manufacture drugs and human biological products in the US or are offered for import into the US market must register their establishment(s) and submit to the FDA a listing of every product in commercial distribution. Foreign establishments must identify a US agent at the time of their registration.

The US enacted the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012 and it requires the FDA to establish a unique facility identifier (UFI) system for both US and foreign drug establishments. After FDA establishes such a system, companies will be required to include a UFI for each establishment in their registrations. Each drug establishment must renew its registration annually. Drug listing information must be updated every June and December. Any changes in the manufacturing of drugs and their packaging are reviewed by the FDA. Manufacturers must notify the FDA in advance of these changes by filing a manufacturing supplement to a new or generic drug application.

THEE STATUTORY POWER OF FDA

The FDA has statutory authority to ensure product safety, effectiveness and compliance with current good manufacturing practices (CGMPs). It has the power to:

  • Seize any drug that is adulterated or misbranded when initially introduced into the market, while in interstate commerce or while held for sale.
  • Enter any factory, warehouse or establishment in which food, drugs, devices, tobacco products, or cosmetics are manufactured, processed, packed or held for introduction into interstate commerce, or to enter any vehicle used to transport or hold such products.
  • Inspect at reasonable times, within reasonable limits and in a reasonable manner, that facility or vehicle and all relevant equipment, finished and unfinished materials, containers and labelling.
  • Collect samples of drug products.
  • Inspect records, files, papers, processes, controls and facilities related to drug products
  • Require production of documents in physical or electronic form in advance of or in lieu of an inspection.
RISK-BASED INSPECTION

As mentioned above, the US amended the Federal Food, Drug and Cosmetic Act (FDCA) which required biennial schedule inspection and replaced it with Food and Drug Administration Safety and Innovation Act (FDASIA) which now allows for inspections with a risk-based schedule for both domestic and foreign facilities based on an establishment’s “known safety risks”. The FDA considers factors including an establishment’s compliance history, the history of recalls related to the establishment, the inherent risks of products produced at the establishment, the frequency of prior inspections of the establishment, and whether the establishment has been inspected by certain foreign governments or agencies. FDA must be notified of any changes to the manufacturing process of any drug or biologic product.

THE HATCH-WAXMAN ACT, GENERIC DRUG APPROVAL & CREATION OF MODERN GENERIC INDUSTRY

The FDA requires generic drugs, to be safe and effective. The Hatch-Waxman Act, formally known as the Drug Price Competition and Patent Term Restoration Act of 1984, expedites and streamlines both generic drug approvals and patent litigation involving generic drugs. Before Hatch- Waxman Act, no streamlined FDA approval process existed for generic drugs. Rather, generic drug companies were required to conduct the same kinds of expensive, time consuming clinical trials that drug companies conducted for new brand-name drugs. In addition, the unlicensed investigation and testing of a patented drug by the generic drug company to obtain FDA approval for a generic version could subject the generic drug company to patent infringement liability. The Hatch-Waxman Act changed this and created an abbreviated process to allow generic drug companies to obtain FDA approval of generic drugs. Because of this, today it is far easier for generic drug companies to demonstrate the safety and efficacy of their generic drugs.

MAIN FEATURES OF HATCH-WAXMAN ACT

The Hatch-Waxman Act has been amended several times since its enactment. Nevertheless, its basic structure remains the same.

Some main features of the Act are:

  • An expedited FDA approval process for generic drug applications.
  • Certain market and patent exclusivity periods for both branded and generic drug companies.
  • Patent term extension to adjust for delays caused by the FDA approval process.
  • A unique patent litigation process triggered by a generic drug company’s submission of an application for FDA approval.

The FDA reviews generic drug applications for compliance with the appropriate scientific and regulatory criteria. If an application meets those criteria, the FDA may grant either:

  • Tentative approval, which means that the application meets the scientific, labelling and
  • Other approval criteria but some unexpired exclusivity prevents final approval
  • Final approval, which is full clearance to enter the market, allowing the applicant to begin selling the generic drug immediately.

Under the Hatch-Waxman Act, generic drug companies can typically file one of two different kinds of abbreviated applications for approval of a generic drug:

  • An Abbreviated New Drug Application (ANDA)
  • A Section 505(b) (2) application, which is often called a paper NDA .
Abbreviated New Drug

Applications: Under this, a generic drug company must establish that the generic drug is effectively a duplicate of the branded, NDA drug, which is referred to as the Reference Listed Drug (RLD). Specifically, the generic drug company must show that the proposed generic drug:

  • Has the same active ingredient, route of administration, dosage form, strength and intended use as the RLD. It also must have the same labelling, except that the generic drug company sometimes may remove information related to a patented method or use subject to exclusivity from its label. However, the generic drug is not required to have the same inactive ingredients as the RLD.
  • Is bioequivalent with the RLD, so that it performs in the same manner as the RLD body. Generally, a drug is bioequivalent when it delivers the same amount of active ingredient in a patient’s bloodstream over the same amount of time as the RLD. Different but analogous rules apply to drugs that are not delivered in the bloodstream, for example, by topical application.
NEW BRANDED DRUG APPROVAL

Before the adoption of the Hatch- Waxman Act, the FDA required branded and generic drug companies alike to demonstrate the safety and efficacy of their products in the same manner through a New Drug Application (NDA). The Hatch- Waxman Act changed certain aspects of the new drug application process and the new drug’s patent term. A branded drug company seeking FDA approval to market a new drug must submit an NDA to the FDA. The information provided in the NDA allows the FDA to determine whether:

  • The new drug is both safe and effective.
  • Certain other regulatory requirements are met, such as those concerning labeling and good manufacturing processes.

Obtaining and submitting this information frequently is a time-consuming process requiring the branded drug company to conduct many extensive and expensive clinical trials. Branded, new drug companies must conduct these trials even though there may be a significant risk that the new drug could fail the clinical trial.

FAILURE OF COMPLIANCE

If a company fails to comply with CGMPs or biologic manufacturing guidelines, the FDA can:

  • Issue an untitled or warning letter
  • Request a product recall
  • Impose an import detention
  • Initiate a seizure action
  • Seek an injunction
  • Impose a clinical hold on any planned or ongoing trials
  • Assess a civil monetary penalty
  • Suspend, revoke or fail to approve an application to market a drug or biologic

According to industry sources, since 2010, the FDA has issued warning letters to an increasing number of companies for lack of compliance. From 2010 to 2012, only five drug manufacturers were cited for violations. But between 2013 and 2015, the number increased to 24. During this time period, the three most common issues cited were a lack of controls to prevent alterations of data by staff, a failure to maintain records of accurate data, and delayed reporting of data.

According to experts, FDA has raised the bar after having adopted new guidelines. They have issued warning to companies all over the world including foreign multinationals. However, the media reports suggest that the violations have been reported more from India and China than from the companies located inside the US. According to a report, of the 29 warning letters sent to drug manufacturers for data integrity problems, 18 were to companies with facilities based in India and six in China. US-based facilities saw just one violation despite receiving 68.8% of all FDA global drug quality inspections between 2010 and 2015.

In India, Natco Pharma has received Form 483 notifications from the US FDA, after the FDA conducted inspections earlier this year at the company’s active pharmaceutical ingredients manufacturing facility at Manali, near Chennai, and the pharmaceutical formulations facility at Kothur, near Hyderabad. According to another media report, the FDA has also warned generic drugmaker Emcure Pharmaceuticals, saying it repeatedly fudged test records at its plant at Hinjwadi, Pune. The FDA had already banned imports from the plant in July last year, except for some drugs, such as cancer medicine carmustine, antipsychotic haloperidol and antibiotic amikacin.

INDUSTRY IMPLICATIONS

As a consequence of FDA tightening noose around the drug companies for violation of best practices, the pharma industry is at present in turmoil. After warning letter to three Indian Laboratories of the Indian pharma company IPCA in January this year, The Global Fund has refused to source antimalarial drugs from the company. IPCA’s Ratlam, SEZ Indore (Pithampur) and Piparia (Silvassa) manufacturing units have been under the FDA scrutiny since July 2014, and they have stopped supplying medicines to the US. This has resulted in a huge loss to the company. Its antimalaria drugs accounted for 24% of its formulation exports in 2015. According to a newspaper report, the Global Fund accounts for about 70% of IPCA’S total institutional business in Africa.

In the future more companies may find their foreign manufacturing operations being scrutinized by FDA. However, the companies that are currently facing problems are trying to address the problem. The companies such as Wockhardt, Sun Pharma, Lupin and IPCA have come together to form a quality forum and are consulting global experts, including both from India and US FDA.

According to DG Shah, Secretary General of Indian Pharmaceutical Alliance, he said in April this year to a newspaper, “We believe that together (FDA and India) we should be able to resolve because FDA is not interested in discontinuing the supply. It hurts the US citizens, because nobody can match the prices that India offers. I do not see that as a problem but it has cropped up and the way FDA is inspecting now is different from how it was being done 12 or 18 months ago. So, we need to take all that into account and work not only on what is now, but we should anticipate what would be the future trend in this and address all those issues and that is what we have started doing.”

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