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ORPHAN DRUGS

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DEFINITION

• “The Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe

and effective treatment, diagnosis or prevention of rare diseases/disorders.”

• The so-called 'orphan drugs' are intended to treat diseases so rare that sponsors are reluctant to develop them under usual marketing

conditions.

• Because the manufacturer wont be able to recover the costs incurred, & it remains in the phase 3 clinical trial , even after the approval from

the Ethics Committee.

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WHAT IS ‘RARE’ ?

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oDepending on the frequency of a disease in the general population:

"Rare" means "less than 1 patient per xxx people."

oDefinition is arbitrary. Authorities in different countries or regions use different cut-off values:• WHO defines an incidence of 0.65-1/1000 as ‘Rare’• US defines <2,00,000 (1/1500) patients as ‘Rare’• EU defines <5/10,000 as ‘Rare’• Japan defines <50,000 as ‘Rare’• Australia defines <2000 as ‘Rare’

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ACTS & REGULATIONS

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• ORPHAN DRUG ACT-The Orphan Drug Act (ODA) of

January 1983, passed in the United States, is meant to

encourage pharmaceutical companies to develop drugs for

diseases that have a small market

• Rare Diseases Act, 2002- establish the Office of Rare Diseases. It also increased funding for the development of treatments for patients with rare diseases.

• European Union(EU)- Committee on Orphan Medicinal Products- broader definition than that of the USA, in that it also covers some tropical diseases

• The Humanitarian Use Device (HUD) program designates a device that is intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4,000 individuals in the United States per year.

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• Orphan Designated Drugs in Clinical Phase: 400

• Marketed Orphan Designated Drugs: 281

• Highest Number of Drugs in Phase-2 Trial: 231

• US Dominates Clinical Trial Process: 350 in Pipeline (Research till Registration)

• Indication for Clinical Trials for Orphan Drug: More than 30% for Cancer Treatment

• Key Market: US (Sales > US$ 40 Billion)

IMPACT OF THE ACTS

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INDIAN PERSPECTIVE

• About 6000-8000 rare diseases, mostly genetic in nature.

• Initial estimation- over 31 million Indians are suffering from rare diseases

• Taking the lower limit of global prevalence estimate, populous nations like India and China should have more than 70 million rare disease cases each.

• With a rare disease population estimated to be around 72,611,605 and with little in place so far, India represents a lucrative market to developers and pharma looking to expand their orphan operations.

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ORGANISATION FOR RARE DISEASES INDIA (ORDI)

• Launched on Feb. 18, 2014

• Theoretically, 400 US FDA & 80 EMA approved orphan drugs- Available

• Practically, most are either not accessible to most patients in India or are unaffordable

• It is ORDI’s mission and hope to make these and new approved orphan drugs easily accessible and affordable to patients with rare diseases in India.

• Currently, drug developers in India are receiving no formal incentives from the Government and hence are more focused on developing affordable drugs

COMPARISON OF ORPHAN AND ESSENTIAL DRUGS

Aspect Essential drugs Orphan drugs

Concrete policies in place since

1977 worldwide 1983:USA 2000: EU

Primary focus Public health Individual patient

Initiated by WHO & member states USA, EU, Japan, Australia

Criteria Drug driven Disease driven

Policies aim to provide

established medicines new medicines to yet untreated patients

Economics Cost effectiveness, sustainable & affordable access

High prices per patient

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PRIORITIES IN BRINGING DRUGS TO PATIENTS

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PREVALENCE OF RARE DISEASES

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CLINICAL TRIALS OF ORPHAN DISEASES

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Scientific Limitations

• Due to the rarity of the disease, a statistically powerful study with a high sample size may not be feasible. "Statistical significance" may be limited.

• Two studies (as otherwise typical) may not be feasible, because the existing patients may hardly be sufficient to fill one study.

• Prognostic factors or disease course indicators might not be known.

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Use of Placebo

• When there is no treatment and the safe investigational drug is the only (even if only theoretical) hope– how can we justify not giving it?

• When the disease will inevitably create damage– how can we justify withdrawing concurrent treatment in order to have a "clean" placebo-controlled study?

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?!

HOW TO APPLY FOR ORPHANDRUG DESIGNATIONA sponsor shall submit two copies of a completed, dated, and signed request for designation that contains the following:

1) A statement that the sponsor requests orphan-drug designation for a rare disease or condition

2) The name and address of the sponsor; the name of the sponsor's primary contact person

3) A description of the rare disease or condition for which the drug is being or will be investigated, the proposed use of the drug, and the reasons why such therapy is needed.

contd..

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HOW TO APPLY FOR ORPHANDRUG DESIGNATION- Contd..

4. A description of the drug, to include the identity of the active moiety, all relevant data from in vitro laboratory studies, preclinical efficacy studies.

5. Where the sponsor seeks approval of an already approved orphan-drug, stating an explanation as to why the proposed variation in his drug may be clinically superior to the first drug.

6. A summary of the regulatory status and marketing history of the drug in the United States and in foreign countries

7. Documentation, with appended authoritative references

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CHALLENGES FACED BY ORPHAN DRUGS

• Difficulties in attracting public and private funding for research and development

• Insufficient numbers of research participants for clinical studies

• Lack of knowledge and training for many rare diseases

• Lack of adequate expertise and review by authorities

• Deficient diagnostic systems

• High price of "orphan drugs"

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Development of Orphan drugs is costlier because:

The limitations of medical and scientific knowledge related to the pathogenesis

A limited market

High research and manufacturing costs (50 to 80 per cent of rare diseases are from genetic origin)

Use of high tech products genetic therapies,

cellular therapies, recombinant proteins

Impossibility of patenting certain ingredients

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INCENTIVES

The incentives include:

• Funding towards investigation

• Tax credit for clinical research

• Waiver of fees for new drug application

• Market exclusivity of “Orphan drugs”

• Accelerated approval or fast track or priority review, may also be available for sponsors of orphan drugs.

• Enhanced patent protection.

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EXCLUSIVITY PERIOD

COUNTRY EXCLUSIVITY TME (YEARS)

USA 7

JAPAN 10

AUSTRALIA 5

EUROPE (EU) 10

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COMPANIES INVOLVED IN THE MANUFACTURE OF ORPHAN DRUGS

Pfizer GlaxoSmithKline Novartis Sanofi Aventis Johnson and Johnson Bayer Orphan drug specialists - Genzyme - Actelion

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ORPHAN DRUGS AND MARKET PLAYERS

DRUG COMPANY THERAPEUTIC INDICATION

Zavesca (miglustat) Actelion Pharmaceuticals US, Inc Type 1 Gaucher’s disease

Trisenox (arsenic trioxide injection) Cephalon, Inc. Acute promyelocytic leukemia (APL)

Aldurazyme (Laronidase) Genzyme Ltd. Mucopolysaccharidosis I

Glivec (Imatinib mesylate) Novartis Philadelphia chromosome positive chronic myeloid leukemia

Fabrazyme (Agalsidase beta) Genzyme Ltd. Fabry disease

Ventavis (iloprost) Actelion Pharmaceuticals US, Inc Pulmonary arterial hypertension (WHO Group I) in patients with NYHA Class III or IV symptoms.

Litak (cladribine) Lipomed Hairy cell leukemia

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CLASSIFICATION OF ORPHAN DRUGS ACCORDING TO INDICATIONS AND COUNTRIESDRUG INDICATIONS COUNTRY

Acetylsalicylic acid Polycythemia Vera Europe

Tobramycin Inhalational Powder/ Solution

Cystic FibrosisPneumonia due to Pseudomonas Aeruginosa

USEurope

Desipramine Chlorhydrate Rett Syndrome Europe

Indomethacin Patent Ductus Arteriosus Japan

Histamine Dihydrochloride Acute Myeloid LeukemiaAcute Erythroid/Promyelocytic Leukemia

EuropeUSA

Contd..

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CLASSIFICATION OF ORPHAN DRUGS ACCORDING TO INDICATIONS AND COUNTRIES- Contd..

DRUG INDICATIONS COUNTRY

Adrenomedullin (AM/ADM) Acute Lung Injury Europe

Acadesine B- Cell leukemiaMultiple Myeloma

Europe

Afamelanotide Solar UrticariaFamilial Benign Chronic Pemphigus

EuropeUSA

Aclotine (Human Antithrombin III) Congenital Antithrombin III Deficiency

France

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ORPHAN DRUGS IN INDIA

• The Hyderabad based NATCO Pharma’s novel anti-cancer drug, NRC-AN-019 has received “ Orphan Drug Designation” from the US-FDA for 3 indications-1. Glioma2. Pancreatic Cancer3. Chronic Myeloid Leukemia contd…

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ORPHAN DRUGS IN INDIA- Contd..

• Troikaa Pharmaceuticals, Ahmedabad manufactures following orphan preparations:

1. Tachyban ( Adenosine injection)

2. Hemaprot (Aprotinin injection)

3. Neopam ( Pralidoxime injection)

4. Narcotam ( Naloxone hydrochloride injection)

5. Cyan SOS (Cyanide antidote kit)

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THE ORPHAN DRUG PIPELINE

ONCOLOGY- BRAND NAME GENERIC NAME

Istodex Romidepsin

Yondelis Trabectedin

Onrigin Laromustine

CENTRAL NERVOUS SYSTEM-

BRAND NAME GENERIC NAME

Zenas Amiframpidine

ITI 111 Midazolam

ANTI-INFECTIVESBRAND NAME GENERIC NAME

Cayston Aztreonam Lysine

ABthrax Raxibacumab

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RECENT DEVELOPMENTS IN REGULATING ‘ORPHAN DRUG’ APPROVAL

• The US FDA & EMA- announced a more streamlined process to help regulators identify and share information in a better way, throughout the development process of orphan drug and biologic products.

• If an orphan product was granted designation on the exact same day in both the US and EU, the sponsors must submit separate reports to their respective regulatory agency.

• Use of one annual report will also benefit sponsors by eliminating the duplication of efforts and by simplifying the process

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CONCLUSION

• Orphan drugs may help pharma companies to reduce the impact of revenue loss caused by patent expiries of blockbuster drugs.

• The new business model of orphan drugs offer an integrated healthcare solution that enables pharma companies to develop newer areas of-

Therapeutics

Diagnosis

Treatment

Monitoring and

Patient Support

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THANK YOU