FDA Drug Master File (DMF) Submission Process

A Drug Master File (DMF) is a submission to the US Food and Drug Administration (FDA) that contains confidential information about a drug product's manufacturing process, raw materials, or analytical methods.

Three Types of DMFs

Type I DMFs: Contain information about facilities, processes, or articles used in manufacturing.

Type II DMFs: Contain information about drug substances (APIs) composition and manufacturing.

Type III DMFs: Contain information about drug product stability.

DMF Submission Process

1. Preparation of detailed documentation
2. Submission via Electronic Submission Gateway (ESG)
3. FDA review and feedback
4. Potential revisions and resubmission
5. Final acceptance and filing

Maintaining a DMF

Regular updates are required to keep information accurate and current. Confidentiality must be maintained through proper security measures.

Benefits of DMF Process

• Streamlined drug development
• Protection of proprietary information
• Quality assurance for drug products
• Regulatory compliance

Challenges in DMF Process

• Complex regulatory requirements
• Significant resource requirements
• Confidentiality management
• Keeping up with regulatory changes

The DMF process is critical for ensuring drug safety and efficacy while protecting manufacturers' proprietary information throughout the FDA approval process.

TGA Approved Paxlovid and Lagevrio: A New Weapon in Australia's Fight Against Covid-19

Australia is soon to be equipped with a new weapon in the battle against Covid-19, but early shortages are expected. Oral medications Paxlovid and Lagevrio, recently approved by the Therapeutic Goods Administration (TGA), are anticipated to be hard to come by in the first few months.

The TGA has granted provisional approval for Pfizer's Paxlovid and Merck Sharp and Dohme's Lagevrio for use in the country. The federal government has ordered approximately 800,000 doses of the antiviral pills, with the first shipments due to arrive soon.

Initial Availability and Supply Constraints

According to Dr. Karen Price, President of the Royal Australian College of General Practitioners (RACGP), there is a global shortage of these medications, which will affect supply in Australia. Dr. Price indicated that initial availability is expected within the month, but larger shipments may take a few months to arrive.

Furthermore, the medications will not be available until they are listed on the Pharmaceutical Benefits Scheme (PBS) and subsidized by the Australian government. This could delay their accessibility to the general public.

Who Can Benefit from Paxlovid and Lagevrio?

The antiviral pills are designed to be taken within five days of symptom onset to prevent severe illness in mild to moderate cases. However, they are not suitable for everyone and are not a substitute for vaccination.

Dr. Price emphasized that the medications are specifically intended for individuals at high risk of developing severe Covid-19, such as those with pre-existing health conditions. Vaccination remains the most effective way to prevent serious illness or hospitalization due to Covid-19.

Regulatory Approvals and Conditions

The provisional approval of Paxlovid and Lagevrio in Australia is subject to strict conditions, including ongoing data submission to the TGA regarding the long-term safety and efficacy of the medications.

Both drugs have also received conditional marketing authorization from the UK's Medicines and Healthcare products Regulatory Agency (MHRA) and emergency use authorization from the US Food and Drug Administration (FDA). Health Canada approved Paxlovid earlier this year.

FDA Approved Sancuso Patch for Chemotherapy Patients

SANCUSO is the first and only FDA-approved prescription patch for the prevention of nausea and vomiting in patients getting particular sorts of chemotherapy therapy.

The active medication in SANCUSO, granisetron, gradually disintegrates in the slender layer of adhesive that adheres to the patient's skin and is delivered into their circulatory system more than a few days, working ceaselessly to prevent chemotherapy-induced nausea and vomiting (CINV).

It is applied 24 to 48 hours prior to getting chemotherapy and can prevent CINV for up to five continuous days. Elective oral medicines should be taken a few times (constantly) to convey similar remedial dosages. "In 2020 there were almost 2,000,000 new instances of disease in the U.S.

What's more every year over a large portion of 1,000,000 Americans go through chemotherapy, with many experiencing the symptoms of their treatment. With SANCUSO, patients are given a basic, simple to apply protection arrangement that doesn't need gulping any pills which can be hard for patients encountering queasiness," said, CEO at Cumberland Pharmaceuticals. "We are respected to assume liability for the brand and present it through our business association, guaranteeing that it is conveyed to the patients who need it."

Under the particulars of the arrangement, Cumberland will obtain U.S. Rights to SANCUSO and will accept full business accountability for the product including its marketing, promotion, distribution, manufacturing and medical support activities.

Net sales of the brand in the U.S. Were more than $14 million out of 2020. The financial terms of the procurement incorporate a $13.5 million installment to Kyowa Kirin after shutting, up to $3.5 million in achievements and layered sovereignties of up to 10% on U.S. Net product deals.

Kyowa Kirin will hold international rights, proceeding to convey the product to address oncology patients' necessities all through the remainder of the world. "Since its send off in 2008, we have set up SANCUSO as a significant strong helpful answer for oncology patients the nation over," said, president of Kyowa Kirin North America. "We accept that Cumberland is all around situated to upgrade the worth of the brand and guarantee that this extraordinary item keeps on conveying significant helpful advantages to oncology patients."

Understanding the Impact of Rising API Costs on Drug Pricing

The SME Pharma Industries' Confederation (SPIC) has said that considering the rising cost of active pharmaceutical ingredients (APIs) and excipients, the maximum price tags of medications should be adjusted according to the changing ingredient cost periodically.

In recent months, the cost of bulk drugs has increased significantly. For instance:

• Paracetamol: Increased from ₹350/kg to ₹900/kg
• Carbamazepine: Rose from ₹2,000/kg to ₹5,500/kg
• Ceftriaxone sterile: Increased from ₹6,600 to ₹8,200
• Tazobactam: Jumped from ₹47,000 to ₹55,000

The maximum price tags for drugs have not been adjusted promptly by the National Pharmaceutical Pricing Authority (NPPA), even when the cost of raw materials exceeds the fixed price of the drug. This lack of adjustment has led to quality concerns in the industry.

"Currently, the situation is the worst it has ever been. Legitimate manufacturers are losing market share," said the secretary general of SPIC in a letter to Prime Minister Narendra Modi. The association has consistently warned about over-reliance on China for APIs.

Bulk pharmaceutical wholesalers have been stockpiling raw materials to profit from price hikes, with no government policy to curb this behavior. The Central Drugs Standard Control Organization (CDSCO) could help address this issue.

"Unless API costs are brought under price control, medication prices should fluctuate with API costs. The government must act to ensure affordable quality generics," the SPIC representative concluded.

Drug Regulatory Reforms in India

The proposed reforms in the existing drug regulatory system in India include provisions for manufacturing and stockpiling of non-COVID vaccines during clinical trials. The Health Ministry's May 18, 2020, announcement marked a significant change by allowing the stockpiling of COVID-19 vaccines during clinical trials, which accelerated the availability of vaccines for public distribution.

Impact on COVID-19 Vaccine Manufacturing

Due to this rule, it became possible to manufacture and stockpile the COVID-19 vaccine during its clinical trials. As a result, millions of vaccine doses were made available in a short span of time, saving countless lives. By the end of 2020, the Serum Institute of India (SII) had already produced around 50 million doses of the Oxford-AstraZeneca COVID-19 vaccine, even while waiting for regulatory approval.

Reforms for Non-COVID Vaccines

Given the success of this provision for COVID-19 vaccines, the same approach should be adopted for non-COVID vaccines. The authorization to use the remaining batches from clinical trials for commercial purposes would ensure that these vaccines are not wasted and can serve a greater purpose after proper regulatory approval.

Draft Rules and Future Implementation

In April 2018, the Health Ministry issued draft rules to allow the commercial use of remaining vaccine batches after clinical trials, under certain regulatory forms. However, these draft rules have yet to be implemented. Rapid enforcement of these rules is essential to prevent the destruction of life-saving vaccines.

Prime Minister's Vision for Regulatory Reform

Following Prime Minister Narendra Modi's vision, a high-powered inter-ministerial commission was established in May 2020 to reform India's drug regulatory system. Recommendations from this commission should be implemented quickly to improve the ease of doing business and advance India's global leadership in vaccine production.

Conclusion

The reforms in India's drug regulatory system, if implemented effectively, have the potential to elevate the country's vaccine industry to new heights. With the right regulatory framework, India can continue its role as a world leader in vaccine production and distribution.

FDA's Accelerated Approval Process: Benefits and Requirements

The FDA has an accelerated approval mechanism for new drugs. Is accelerated FDA approval a good thing? Probably Yes. This mechanism of approval was put into place to help patients who suffer from certain serious diseases.

As the phrase suggests accelerated FDA approval involves a faster approval than for non-accelerated approvals. To get an accelerated approval sponsors must submit their application to the FDA. Before an application is accepted for approval, two major regulatory tests described below are applied.

THE DRUG HAD TO TARGET SERIOUS CONDITIONS

What is a serious condition? If you are a patient almost every disease would be a serious condition. The FDA has clarified this in a guidance document.

This is a disease or condition which has significant impacts on a person's day-to-day ability to function or even die.

Clinical judgment has to be made in determining whether a disease is serious or not.

The judgment is based on the impact of the disease on factors such as the patients' survival and day-to-day functioning. In addition, an assessment is made on the likelihood that the disease will progress to a more severe condition if no treatment is provided.

There are other three pathways for expedited approval of NDA which require establishment of serious condition. They include fast track, breakthrough therapy and priority review.

All diseases that are life threatening qualify as serious illnesses but not necessarily for accelerated FDA approval as we will see later. Some will qualify for fast track, breakthrough therapy and priority review but not for accelerated approval.

THE DRUG HAD TO BE FOR AN UNMET MEDICAL NEED

The term "unmet Medical Need" is used to refer to a medical condition that does not have adequate treatment or diagnosis. It may be for treatment of cancer or a method for better and faster diagnosis of a serious illness. The application of the term "unmet medical need" could be quite broad.

The term "unmet medical need" could be used where there is no available appropriate treatment to the patients. Sometimes a new therapy may be available but unmet medical need may still exist such as when the new reduces the symptoms but not the serious outcome such as progressive disability or progression of the illness.

WHAT THE SPONSOR SHOULD DO

Because many sponsors may want to use accelerated FDA approval, certain pre-qualification criteria have been put into place.

As the accelerated FDA approval application is based on surrogate endpoints. Sponsors should ordinarily discuss with the FDA of the intention to request for accelerated approval.

The request would help the sponsor to choose the best surrogate endpoints during the clinical trials. Surrogate endpoints are endpoints other than clinical endpoints which take longer to determine for diseases that take long to show a clinical endpoint.

For example, it might take long to show that a drug prolongs life. Prolongation of life is a clinical endpoint. Decrease in the blood in viral load such as in HIV would be a surrogate endpoint.

Surrogate endpoints include laboratory measurements and images among others. The use of clinical endpoints is however required in the confirmatory clinical trial reports.

By the time this application is being submitted the sponsor should be in a position to discuss the confirmatory clinical trials which should be in progress.

Without evidence of these confirmatory trials the FDA may be reluctant to approve the requested accelerated FDA approval. The risk to patients is exposure to expensive drugs which may offer no clinical benefits. The sponsor must provide evidence for commitment to complete the pending confirmatory trials.

Does Canada have a similar program to accelerated FDA approval? The Canadian equivalence is called priority review. In this program the sponsor is encouraged to request for priority review status early. The sponsor will get a notice of compliance status with conditions after the application when the only data available is from surrogate end-points.

The target review period is 200 days. Just as in USA, the sponsor has to submit confirmatory clinical trial data for full compliance without conditions.

Understanding the Drug Development Process

Have you ever wondered where the medicines we take come from? How do doctors determine which drug is suitable for a specific disease? How are medicines able to cure the ailments they are prescribed for? Let’s explore the drug development process from the beginning.

Drug Development Phases

The development of drugs involves clinical research and several phases of testing. These phases are designed to provide evidence for the efficacy and safety of a drug. The process starts with drug design and molecule discovery and progresses through various stages, including animal and human testing.

Pre-Clinical Study

When a drug molecule is identified, it undergoes in vitro (test tube or cell culture) and in vivo (animal) experiments to assess its preliminary efficacy, toxicity, and pharmacokinetics. This phase helps pharmaceutical companies determine which molecules have the greatest potential for further study.

Phase 0 Study

Also known as micro-dosing trials, this phase involves administering single sub-therapeutic doses to a small group of 10-15 human subjects. The goal is to gather pharmacokinetic data to decide whether to proceed with further development. If the data is promising, an Investigational New Drug (IND) application is submitted to the FDA.

Phase I Study

Also known as First-in-Man studies, this phase tests the drug's safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in 2-100 healthy subjects. It includes:

• Phase Ia: Single ascending dose studies.
• Phase Ib: Multiple ascending dose studies.

Phase II Study

This phase involves enrolling over 100 diseased subjects to evaluate the drug’s efficacy and safety over a longer period. This phase is also known as "Proof of Concept" or "Pilot" studies and can result in the drug’s failure if the results are not as expected or if there are significant side effects.

• Phase IIa: Pilot study to assess clinical efficacy or biological activity.
• Phase IIb: Dose-finding study to determine the optimal dose with minimal side effects.
• Combined trials, such as Phase I/II, can also be conducted to evaluate efficacy and toxicity.

Phase III Study

This phase involves large-scale testing to confirm the drug’s effectiveness, monitor side effects, and compare it with existing treatments. Data from Phase III trials is critical for regulatory approval.

Phase IV Study

Post-marketing surveillance ensures the drug’s long-term effectiveness and safety once it is available to the public. This phase helps to monitor any long-term effects or rare side effects.

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