Regulatory IssuesUS and Abroad

BIT 230

Chapters 9-11 Huxsoll

Regulatory Affairs

Separate discipline that is part of product development team

Know laws enforced by FDACertain area of FDA presides over your

productLiaison between company and

government - CSO (Consumer Safety Officer)- point person from FDA

FDA

Review - law enforcement agency charged with the health and safety of food, drugs, cosmetics, medical devices

Division CDER - drugs CBER - biologics CDRH - devices/radiologic health CVM - veterinary medicine CFSAN - food safety and applied nutrition

FDA

SAFETY and

efficacy

FDA

Burden of proof for safety and efficacy evidence from product sponsor

FDA decides if there is enough evidence to approve product

needs ‘substantial evidence” (between preponderance of evidence and beyond a reasonable doubt)

rules often reactive to a crisis

FDA activities

Rulemaking - formulating, amending or repealing a rule disseminating info. To public

Adjudication - agency process for the formulation of an order (telling someone what to do responds to sponsor’s application for approval

to the FDA

Guidelines & Points to Consider

Guidelines - procedures and standards acceptable to the FDA communicate info that FDA has vast experience

Points to Consider - areas where FDA has little experience

Guidelines and PtC not enforceable requirements (like other aspects of FDA)

Product Characterization

See pages 142-143 -product definitionsDrug

cure, diagnose, treat prevent

Device instrument, apparatus, machine, implant,

reagent

Biological product virus, serum, toxin, vaccine, blood product

Regulatory functions

SubmissionsComplianceEnforcementMiscellaneous

Submission

File application with the FDANDA - new drug application - product not

yet recognized as safe and effectiveDevices - Class O, II, III; I and II need a

Premarket Notification- 90 day notice before goes into market; Class III needs FDA approval before commercial marketing begins

Submission cont’d

Biological products - requirements specialPLA - product license application, to

describe the productELA - establishment license application -to

describe the facilities used to manufacture the product

Submission cont’d

Remember three areas:

premarketing (IND)marketing (NDA)postmarketing (after on the market)

Compliance

GLP nonclinical laboratory studies

GMP set of rules for drugs, medical devices and

biologics

GCP inform subjects of test product in clinical trials

Other compliance areas

Study/data audits review raw data in reports

corporate policies and procedures self-imposed procedures for compliance

submissions commitments especially to coordinate manufacturing facilities

in different countries

Compliance

3 key points:

documentationdocumentationdocumentation

Enforcement

Civil or criminal penaltiesProduct liability suitsFrom Huxsoll page 147:

“ Enforcement is the end result of a lack of integration. It implies a failure in the systems designated to prevent mistakes and inadvertent or untested changes.”

Miscellaneous

State requirements for compliance (in addition to federal)

e.g in book- California State Board of Pharmacy says pharmacist responsible for manufacturing

State and federal laws for controlled substances

Incentives for orphan products

European Regulatory Issues

Chapter 10

One Europe

1995 “mutual regulation” for drug regulation by EU members

European Medicines Evaluation Agency (EMEA) - administering centralized procedure

Submit to agency and can get simultaneous approval in many European countries (for highly innovative products)

Other Products

Conventional products - submit filing to country of choice

Once approved there, other members of the EU will recognize the drug’s registration

Send to central agency only if concerns about original registration in Europe

European Drug Market

Small continent in comparison to some others, but one of largest drug markets outside the US (total population of Europe estimated at 400 million, down from # in textbook of close to 700 million)

Uses many medicinesApproval may be faster in EuropeRU 486 example

EC

1957 European Economic Community

France, Germany, Belgium, Italy, Luxembourg and Netherlands

Formed to achieve harmonization of laws and regulations for bringing drugs to market

Special organizations

Concertation procedure, for marketing products Recombinant DNA products transformed lines hybridoma and monoclonal antibody

procedures Referred to the CPMP (Committee for

Proprietary Medicinal Products)

Approval

Europe faster approval time lines than US (although not much; 417 vs. 452 days for US

For recombinant products, 411 in Europe vs. 548 days for approval in US’

FDA faster than EMEA on monoclonal antibody approval

Approvals cont’d

EMEA doesn’t have priority review like FDA does; may try and implement such a review

See and review handout from Tufts about EU/EMEA summary

Regulatory Issues in Japan

Chapter 11

The Ministry of Health & WelfareOversees social welfare, social security

and public health in JapanMade up of several bureaus, local

branches and affiliationsPAB(Pharmaceutical Affairs Bureau) one

of bureau for drugsPage 174 - chart (DO NOT need to know!)

PAB

Supervises domestic & foreign drug-related products

Director General of the PAB similar to head of FDA

8 divisions within PAB to deal with various aspects (biologics & antibiotics, safety, etc.)

Many functions similar to US (fee page 175)

CPAC

Central Pharmaceutical Affairs CouncilPowerful agency within ministryGovernment advisory committeeMakes recommendation for final approval

for drug manufacturing and importation of foreign drugs

Standards for Production

Japan has GLP, GMP and GCP regulations

for GCP, has guidelines for 14 therapeutic areas (page 177- DO NOT need to know)

Some bilateral agreements with countries to ensure quality

Several agencies within Japan work together develop guidelines

Drug Registration

Before 1983, formal partnership was needed with a Japanese country

1983 amendment, foreign drug producers can apply directly to import and sell drugs in Japan

Japan (along with Europe) prescribe our drugs

Terms

See page 181Cell culture, Seed cell lines, MCB and Cell

banks - similar definitions to the US terminology

CPAC says biologics should be considered entirely new drugs - must undergo complete preclinical and clinical testing again.

Manufacturing Criteria

Define origin and characteristics of seed cell line

Define method of prep, storage and maintenance of MCB

QA issuesStability of cells being used

Clinical Studies

Japan uses Phase I, II, and III testingSame as ours:

Phase 1: pharmacokinetics in healthy patients Phase II: small group with disease to look at

efficacy and continue looking at safety Phase III: larger group of patients with disease

to look at efficacy

Canada

Parallels drug approval process of FDA in US

Canadian drug approval

Why are drugs cheaper in Canada?

Canadian drug costs